1Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, UCM, Ciudad Universitaria, 28040 Madrid, Spain
2Centro de Investigación del Cáncer, IBMCC, Universidad de Salamanca-CSIC, 37007 Salamanca, Spain
Phone: +34 91 394 1627
Fax: +34 91 394 1779
Phone: +34 92 329 4801
The family of p38 mitogen-activated protein kinases (MAPKs) belongs to the MAPK superfamily. They are strongly activated by different stress signals and inflammatory cytokines, although non-stressful stimuli also activate p38 MAPKs leading to the regulation of cellular functions such as proliferation, differentiation and survival. Four different p38 MAPK family members have been identified so far: p38α, β, γ and δ, also known as stress-activated kinase 2a (SAPK2a), SAPK2b, SAPK3 and SAPK4, respectively, which may have both overlapping and specific functions (reviewed by Cuenda and Rousseau, 2007; Kyriakis and Avruch, 2001; Nebreda and Porras, 2000; Ono and Han, 2000).
p38α was initially identified as a 38 KDa protein, which became phosphorylated in Tyr in response to the bacterial endotoxin LPS in macrophages (Han et al., 1994). In parallel, other two groups identified p38α as a kinase activated by stress and IL1, able to phosphorylate and activate MAPKAP-K2 (MAPK-activated protein kinase 2) (Freshney et al., 1994; Rouse et al., 1994). p38α (encoded by MAPK14 gene) is broadly expressed and is also the most abundant p38 isoform present in most cell types. Targeted inactivation of the mouse p38α gene results in embryonic death due to a placental defect (Adams et al., 2000; Mudgett et al., 2000; Tamura et al., 2000).
p38 MAPKs are mainly activated by MKK3 and MKK6 through dual phoshorylation in Tyr and Thr, although MKK4 can sometimes activate p38α (Cuenda and Rousseau, 2007). MKK3 and MKK6 are in turn activated by phosphorylation by a MAPK kinase kinase (MKKK) such as MLKs, ASK1, TAK1 or MEKKs, which are activated by small and heterotrimeric G proteins (Cuenda and Rousseau, 2007; Wagner and Nebreda, 2009).
p38α can be also activated through MKK-independent pathways such as that involving p38α autophospohorylation upon interaction with TAB1 (Cuenda and Rousseau, 2007).
Once p38 MAPKs are activated, they phoshorylate different transcription factors such as p53, ATF2, MEF2 or C/EBPb and protein kinases, including MAPKAP-K2 and MAPKAP-K3 (also known as MK-2 and MK-3), MSK-1 (mitogen- and stress-activated protein kinase 1) and MNK-1 and MNK-2 (MAP kinase-interacting serine/threonine kinase 1 and 2) (Cuenda and Rousseau, 2007; Wagner and Nebreda, 2009).
The analysis of the function of p38α has been initially based on the effect of chemical inhibitors such as SB203580 and SB202190, which inhibit p38α but can also inhibit p38β at a higher dose (reviewed by Nebreda and Porras, 2000). Therefore, the main effects observed upon treatment with those inhibitors are a consequence of p38α inhibition, sometimes are also due to p38β inhibition. The generation of mice with specific genetic inactivation of the different p38 isoforms or the use of interference RNA technology during the last few years has allowed a more precise study of the role played by each isoform and they have been essential to establish the role of p38α in different cellular processes.
Figure 1. p38 MAPK signaling pathway. A variety of stimuli, mainly stress stimuli, activate p38 MAPK through complex kinase cascades including a MAP3K that phosphorylates a MAPK2 that, in turn, phosphorylates p38MAPKs. Cellular intermediates, like GTPases, receptor adapter proteins or cell cycle checkpoint proteins, among others, transmit the stimulus to the kinase cascades. Once activated, the different p38MAPKs either phosphorylate cytoplasmic targets or translocate into the nucleus leading to the regulation of transcription factors involved in cellular responses. MKK6 is the major activator of all p38 MAPK isoforms, while MKK3 and MKK4 are more specific and can only activate some isoforms.
2- Dual role of p38 MAPK in cell death: function of p38α in apoptosis
p38 MAPK can play a dual role as a regulator of cell death, thus it can either mediate cell survival or cell death through different mechanisms, including apoptosis. Therefore, the specific function of p38 MAPKs in apoptosis appears to depend on the cell type, the stimuli and/or the isoform (reviewed by Nebreda and Porras, 2000; Wagner and Nebreda, 2009).
As indicated above, some studies have been based on the using of chemical inhibitors such as SB203580 which is able to inhibit p38α and p38β, thus the participation of the p38β isoform in apoptosis can not be excluded. In fact, there is a good evidence for a role of p38α and/or p38β MAPKs as mediators of apoptosis in several cell types such as neurons (Ciesielski-Treska et al., 2001; De Zutter and Davis, 2001; Ghatan et al., 2000; Le-Niculescu et al., 1999) or cardiac cells (Mackay and Mochly-Rosen, 1999; Saurin et al., 2000; Wang et al., 1998). Moreover, the induction of apoptosis by many types of stimuli such TNF-α (Valladares et al., 2000), TGF-β (Edlund et al., 2003) or oxidative stress (Zhuang et al., 2000) involves one of these p38MAPKs.
p38α is a mediator of apoptosis in response to a number of cellular stresses through transcriptional and posttranscriptional mechanisms, which can involve the regulation of apoptotic and/or survival pathways (reviewed by Wagner and Nebreda, 2009). For example, p38α sensitizes cardiomyocytes and MEFs-derived cell lines to apoptosis induced by different stimuli through both, up-regulation of the pro-apoptotic proteins Fas and Bax and down-regulation of the activity of ERKs and Akt survival pathways (Porras et al., 2004; Zuluaga et al., 2007a). According to this, overexpression of p38α enhances apoptosis induced by the constitutive active mutant MKK3bE in cardiomyocytes, while overexpression of p38β promotes cell survival (Nebreda and Porras, 2000).
p38α is also a negative regulator of survival in embryonic stem (ES) (Guo and Yang, 2006). In addition, p38α is able to suppress tumor initiation induced by H-ras oncogene through induction of apoptosis (Dolado et al., 2007). Upon expression of oncogenic H-Ras, ROS are generated leading to p38α activation and apoptotic cell death. Moreover, p38α MAPK plays an important role in the apoptosis induced by some chemotherapeutical drugs. For example, it is essential for cisplatin-induced apoptosis in the colon carcinoma derived cell line, HCT116 (Bragado et al., 2007).
On the other hand, anti-apoptotic roles of p38 MAPKs have been described in DNA-damaged fibroblasts (Héron-Milhavet and LeRoith, 2002), differentiating neurons (Okamoto et al., 2000) and activated macrophages (Park et al., 2002). In some cases, p38α has been identified as the isoform responsible for this survival effect. For example, in pulmonary arterial endothelial cells exposed to anoxia-reoxygenation during ischemia-reperfusion, carbon monoxide (CO) protects from apoptosis through p38α activation (Zhang et al., 2003; Zhang et al., 2005). In response to H2O2, p38α also mediates cell survival in MEFs, while p38α mediates apoptosis triggered by serum deprivation (Gutiérrez-Uzquiza et al., 2010). In both situations, C3G acts as a negative regulator of p38α. This crosstalk between the C3G and the p38α pathways has been also observed in CML cell line K562, where p38α mediates STI-571-induced apoptosis (Maia et al., 2009).
In contrast to the apoptotic role of p38 in CML cells treated with STI-571, p38 MAPK pathway exerts an antiapoptotic role in CML cells, as well as acute promyelocytic leukemia cells (APL), treated with arsenic trioxide (AT) (Verma et al., 2002b).
In some tumor cells p38α can also induce a pro-survival effect known as tumor dormancy, which maintains cells in a quiescent state related to drug resistance (reviewed by Aguirre-Ghiso, 2007). In addition, p38α can also induce cell survival of colorectal cancer cells through inhibition of autophagy (Comes et al., 2007).
3- Pathways regulating p38α apoptotic function
There are different signaling pathways that are involved in the regulation of p38 apoptotic function. Some of them can be considered classical and/or canonical, while others such as C3G-Rap1 or PKC are novel or less known.
Classically, two small GTPases from the Rho family, Rac1 and Cdc42, have been described to be activators of p38α MAPK (Nobes and Hall, 1995). The existence of a functional crosstalk between Rac and p38 MAPK has been largely reported in relation with different cellular functions. p38 can act either as an effector or as an activator of Rac. In particular, in cardiomyocytes p38α acts as a positive or a negative regulator of Rac1 depending on the presence of growth factors (Zuluaga et al., 2007b). On the other hand, Rac-GTP induces p38 activation in many systems (Nobes and Hall, 1995). For example, Rac-1 is an upstream regulator of p38 in retinoic acid-induced differentiation and apoptosis of malignant NB-4 (acute pro-myelocytic leukemia) and MCF-7 (breast carcinoma) cell lines (Alsayed et al., 2001).
Recent novel findings support the participation of another member of the Ras family, the GTPase Rap1, in the regulation of p38α function in apoptosis (Gutiérrez-Uzquiza et al., 2010; Maia et al., 2009). Rap1 can either activate or inhibit p38α depending on the cell context. In CML cells, the C3G-Rap1 pathway downregulates the pro-apoptotic activity of p38αMAPK as a mediator of STI effects (Maia et al., 2009). In contrast, in MEFs C3G is a negative regulator of p38α MAPK activity and Rap1 a positive one, leading to pro- or anti-apoptotic effects depending on the stress stimulus (Gutiérrez-Uzquiza et al., 2010).
There are also evidences of a cross-talk between PKCs and p38 MAPK in order to regulate apoptosis. For example, in LNCaP prostate cancer cells, PMA induces apoptosis through a mechanism, which involves PKCα and d-mediated p38α/β activation (Tanaka et al., 2003). An autocrine pro-apoptotic loop is also generated in these cells by PKCδ, which is mediated by death receptor ligands through a mechanism dependent on caspase-8, FADD, p38α/β MAPK and JNK (Gonzalez-Guerrico and Kazanietz, 2005). In addition, in vascular smooth muscle cells activation of PKCδ leads to apoptotic cell death involving p53 induction through a mechanism partially dependent on p38α/β MAPK (Ryer et al., 2005).
4- Targets of p38α in the regulation of apoptosis
The mechanisms by which p38α can mediate apoptosis or cell survival, include those involving the regulation of the expression and/or activity of different members of the Bcl-2 family.
Bax is a pro-apoptotic member of the Bcl-2 family, which can be regulated by p38α through different mechanisms. In cardiomyocytes derived cell lines, p38α mediates an up-regulation of Bax mRNA and protein, which sensitizes cells to apoptosis induced by different stimuli (Porras et al., 2004). In addition, in primary neonatal cardiomyocytes p38 (α/β) mediates Bax translocation to mitochondria upon simulated ischemia (Capano and Crompton, 2006). This p38 (α/β)-induced Bax translocation was also observed in a human hepatoma cell line (HepG2) treated with different pro-apoptotic stimuli (Kim et al., 2006). In contrast, in the anoikis-induced apoptosis in mammary epithelial cells, p38α is not required for Bax mitochondrial translocation, but it acts as a part of a mitochondrial complex allowing Bax activation and cytochrome-c release (Owens et al., 2009).
Bim levels (Cai and Xia, 2008) and activity (Cai et al., 2006) are also positively regulated by p38α, which contributes to induce apoptosis. Thus, in PC12 cells treated with sodium arsenite, p38α induces FOXO3a nuclear translocation, which stimulates Bim transcription, leading to an increase in BimEL protein levels (Cai and Xia, 2008). In addition, p38α contributes to BimEL phosphorylation in Ser65 (Cai et al., 2006).
Bcl-2 has been shown to be phosphorylated by p38α upon NGF withdrawal in memory B lymphocytes, which leads to inhibition of its anti-apoptotic activity and to induction of cytochrome-c release (Torcia et al., 2001). Similarly, H2O2 induces p38α-mediated Bcl-2 phoshorylation in adult rat cardiac myocytes contributing to apoptosis (Markou et al., 2009).
p38 can also mediate survival through regulation of the expression and/or activity of proteins from the Bcl-2 family. For example, carbon monoxide protects from ischemia-reperfusion lung injury through a p38α-dependent up-regulation of Bcl-2 and Bcl-xL protein levels (Zhang et al., 2003). According to this, UVA-induced p38 (α/β) activation in a human keratinocyte cell line (HaCaT cells) results in an increase in Bcl-xL protein levels through post-transcriptional mechanisms mediated by the 3'-unstranslated region (UTR) (Bachelor and Bowden, 2004). In addition, in primary human trophoblasts p38 appears to mediate EGF-mediated Bad phosphorylation in Ser 112, which protects from hypoxia-induced apoptosis (Humphrey et al., 2008).
p38α is also involved in the stimulation of Fas and FasL expression, which can contribute to apoptosis in a number of cellular systems. p38α was shown to participate in the anti-CD3-induced upregulation of Fas and FasL expression in T cells, although p38α alone was unable to increase Fas expression (Hsu et al., 1999). Similarly, p38 MAPK is a mediator of hepatitis B virus X protein-induced Fas and FasL expression (Wang et al., 2004). p38α activation also mediates Fas expression through phosphorylation of STAT1 in Ser-727 in cardiac myocytes exposed to ischemia/reperfusion (Stephanou et al., 2001). According to this, Fas expression is down-regulated in p38α-deficient embryonic cardiomyocytes under basal conditions which contributes to sensitize cells to apoptosis (Porras et al., 2004). In contrast, p38 downregulates Fas expression through inhibition of NF-kB in human melanoma cells (Ivanov and Ronai, 2000).
Apart from the role of p38α in the regulation of Fas/FasL expression, p38α mediates caspase 8 activation in Fas-activated Jurkat cells by inhibiting the phoshorylation and presence of c-FLIPs in the DISC (Tourian et al., 2004). p38 also mediates TGF-β-induced activation of caspase 8 (Schrantz et al., 2001) as well as the regulation of membrane blebbing and nuclear condensation (Deschesnes et al., 2001).
The tumor suppressor protein p53, which is a relevant mediator of apoptosis in response to a great variety of stimuli, is also an important p38 target. In fact, there are a number of evidences supporting a role for p38α in the regulation of p53. For example, in response to different chemotherapeutic drugs such as cisplatin p38α phoshorylates and/or activates p53 leading to onset of apoptosis (Bragado et al., 2007; Sánchez-Prieto et al., 2000). p38α can also induce apoptosis through p53 in response to other stimuli,. Thus, p53 phosphorylation by p38α is essential in the apoptosis induced by the HIV-1 envelope (Perfettini et al., 2005). In addition to this role of p38α as a direct regulator of p53, p38α also acts through phosphorylation and stabilization of the p53 coactivator, p18Hamlet (Cuadrado et al., 2007). In response to DNA damage p18Hamlet is accumulated, which contributes to induce apoptosis through the stimulation of some p53-regulated genes, such as Noxa.
Other alternative mechanisms are involved in p38α-mediated apoptosis. For example, phosphorylation of H2AX by p38α has been shown to be required for serum starvation-induced apoptosis (Lu et al., 2008).
In addition to the above referred effects of p38α through direct regulation of pro- and/or antiapoptotic proteins, p38α is also a negative regulator of PI3K/Akt and ERKs survival pathways. Thus, in p38α-deficient derived cardiomyocytes or MEFs cell lines ERKs and Akt activities are increased, which contributes to the enhanced survival of these cells (Porras et al., 2004; Zuluaga et al., 2007a). In particular, in cardiomyocytes p38α can negatively modulate Akt activity, independently of PI3K, favoring the interaction between caveolin-1 and PP2A and the activation of PP2A through a mechanism dependent on cell attachment (Zuluaga et al., 2007a).
There are additional mechanisms that can be involved in the p38α-induced survival, such as the activation of the ATF6α-Rheb-mTOR survival pathway (Schewe and Aguirre-Ghiso, 2008). Other mechanisms include the p38α mediated induction of antioxidant enzymes expression in response to oxidative stress (unpublished data from our group). In addition, the increase in BNIP-3 levels and the low Bim/Bcl-xL ratio induced by p38α would contribute to this survival effect upon H2O2 treatment (Gutiérrez-Uzquiza et al., 2010).
Figure 2. Mechanisms involved in p38α-mediated apoptosis. p38α induces the expression of pro-apoptotic proteins such as the death receptor, Fas and its ligand, FasL, as well as Bax, Bim or Noxa from the Bcl-2 family. This expression is induced by the phosphorylation of transcription factors, such as p53 and/or coactivators such as p18Hamlet. This would lead to the activation of the Fas death receptor pathway and the mitochondrial pathway. p38α can also activate some of these pro-apoptotic proteins, such as Bim, through phosphorylation or through alternative mechanisms as it happens for Bax. Alternatively, p38α can inhibit c-FLIP phosphorylation impairing its function as an inhibitor of caspase 8 activation. p38α can also inactivate the anti-apoptotic protein Bcl-2 through phosphorylation. In addition, p38α negatively regulates ERKs and Akt survival pathways, being PP2A the mediator of Akt inactivation.
5- Disregulation of p38α function in apoptosis: involvement in human diseases
Different evidences from the literature indicate that the pro-apoptotic function of p38α is deregulated in some human diseases such as cancer, although recent findings have also linked p38 signaling with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson disease (PD) and amyolotrophic lateral sclerosis (ALS) (reviewed by Kim and Choi, 2010).
5.1- Role of p38α in cancer: implication in cancer development and therapy
5.1.1- p38α as a tumor suppressor and/or mediator
Several data indicate that p38α can act as a tumour suppressor (Review by Wagner and Nebreda, 2009). In particular, p38α negatively regulates malignant transformation induced by Ras through different mechanisms including apoptosis induction. For example, in MEFs expressing H-RasV12, sustained activation of p38α MAPK inhibits transformation through a mechanism involving ROS-induced apoptosis (Dolado et al., 2007). H-RasV12-induced ROS is only able to trigger apoptosis in MEFs expressing p38α, but not in those deficient in this protein. As a consequence, p38α-deficient MEFs transformed by Ras accumulate high levels of ROS which contributes to tumour progression. This type of response is produced in the transformation induced by different oncogenes able to generate ROS. In fact, many human cancer cell lines have developed mechanisms to uncouple ROS generation to p38α activation and therefore induction of apoptosis. However, as referred above, p38α can also induce a survival state known as tumor dormancy in some cancer cells such as those from squamous carcinoma, which maintains cells in a quiescent state related to drug resistance through mechanisms including activation of the p38α-ATF6α-Rheb-mTOR survival pathway (reviewed by Aguirre-Ghiso, 2007; Schewe and Aguirre-Ghiso, 2008).
5.1.2- Role of p38 in chronic myeloid leukemia and other hematopoietic malignancies
p38 MAPK, mainly the p38α isoform, is a key player in the maintenance of hematopoiesis homeostasis, as it balances both proliferative and growth inhibitory signals triggered by the growth factors and cytokines that regulate normal hematopoiesis (Feng et al., 2009; Uddin et al., 2004). Alterations in this p38 MAPK-controlled balance may result in either overproduction or depletion of myelosuppressive cytokines leading to the development of certain bone marrow failure syndromes. For example, p38α is responsible for the enhanced stem cell apoptosis characteristic of low grade myeolodysplastic syndromes (MDSs) (Navas et al., 2006; Zhou et al., 2007). On the other hand, imbalance toward the proliferative side may conduct to the development of myeloproliferative syndromes (MPSs), such as leukemia, lymphomas and myelomas.
The role played by different members of the p38 kinase family in the regulation of acute leukemia blasts growth (myeloid and lymphoid), is not well defined, although they seem to participate in the generarion of resistance to chemotherapeutic agents (Feng et al., 2009; Platanias, 2003) In contrast, the participation of the p38 MAPK pathways in the pathogenesis and pathophysiology of chronic leukemias have been extensively studied, although its role is contradictory. On one side, p38 is activated by the Rho-GEF domain of Bcr, contributing to transformation through the regulation of NF-κB activation (Korus et al., 2002). On the other side, p38 MAPK is selectively activated by IFNα and mediates the growth suppressive effects of IFNα in CML cells (Mayer et al., 2001) as well as in normal hematopoiesis (Verma et al., 2002a).
p38 MAPK also seems to play a role in chronic lymphocytic leukemia (CLL). p38 and its effector MK-2 (MAP kinase-activated protein kinase-2) are activated by rituximab in cultures of CLL cells and contributes to the generation of the antileukemic effects of rituximab in CLL (Pedersen et al., 2002). Finally, there are evidences supporting the participation of p38 in cell proliferation and adhesion of lymphomas and multiple myelomas in response to growth factors (Feng et al., 2009; Platanias, 2003).
Another important function of p38α MAPK in hematopoiesis is to promote cell differentiation. Curiously, while GTP-induced erythroid differentiation of K562 cells is mediated through p38-dependent caspase activation (Moosavi et al., 2007), caspases do not participate in STI-571-induced erythroid differentiation in CML cells, where STI-571-mediated apoptosis and differentiation are independent events (Jacquel et al., 2007). The differentiation-inducing therapy may be a good therapeutical alternative for CML patients that develop resistance to STI-571.
5.2- Role of p38α in neurodegenerative diseases
Recent findings support the involvement of p38 MAPK signaling pathway in neurodegenerative diseases. Thus, persistent activation of the p38 MAPK signaling has been suggested to contribute to neuronal apoptosis in Alzheimer's disease (AD), Parkinson disease(PD) and Amyotrophic lateral sclerosis (ALS).
Alzheimer's disease is an incurable, neurodegenerative disease characterized by a progressive deterioration of the congnitive, memory and learning ability including lost of motor coordination at advanced stages. AD is the result of the accumulation of plaques containing amyloidogenic Aβ proteins and tangles containing the microtubule-associated protein tau in a hiperphosphorylated state (Giacobini and Becker, 2007). The ASK1-MKK6-p38 signaling pathway participates in amyeloid precursor protein (APP) and tau phosphorylation in response to oxidative stress and contributes to the expression of the β-secretase gene (Galvan et al., 2007) and the induction of neuronal apoptosis triggered by ROS (D'Amico et al., 2000; Puig et al., 2004; Tamagno et al., 2003).
Parkinson disease is a degenerative disorder of the central nervous system characterized by muscle rigidity, tremor and loss of physical movement caused by a progressive loss of dopaminergic neurons. A number of specific genetic mutations causing Parkinson's disease have been discovered, being the mutations in α-Synuclein (a major constituent of Lewy bodies) among the best characterized (Gandhi and Wood, 2005). α-Synuclein activates p38 MAPK in human microglia promoting a potent inflammatory stimulation of microglial cells (Klegeris et al., 2008). The p38 MAPK is also activated in PD cellular and animal models and plays a role in dopaminergic neural apoptosis through the phosphorylation of p53 and expression of the pro-apoptotic protein Bax (Karunakaran et al., 2008; Mathiasen et al., 2004; Silva et al., 2005).
Amyotrophic lateral sclerosis is a progressive, lethal, degenerative disorder of motor neurons in the brain and spinal cord, leading to paralysis of voluntary muscles. Aberrant chemistry and oxidative stress have been described to be involved in ALS development, being SOD1 (superoxide dismutase 1) the most frequently mutated gene in the inherited cases of ALS. Numerous evidences point to a role of p38 MAPK in the development and progression of ALS induced by mutations in SOD1 gene (Bendotti et al., 2004; Bendotti et al., 2005; Dewil et al., 2007; Holasek et al., 2005; Tortarolo et al., 2003). Mutant SOD1 provokes aberrant oxyradical reactions that increase the activation of p38 MAPK in motor neurons and glial cells. This increase in active p38 MAPK may phosphorylate cytoskeletal proteins and activate cytokines and nitric oxide, thus contributing to neurodegeneration through different mechanisms including apoptosis (Bendotti et al., 2005; Tortarolo et al., 2003).
5.3- p38α in cancer therapy
p38α can act as a tumor suppressor in the initial phases of malignant transformation, which involves apoptosis induction. Similarly, p38α is also a mediator of apoptosis upon treatment with many chemotherapeutical drugs such as cisplatin, arsenic trioxide or others. Therefore, p38α can be considered as a target in the treatment of cancer, although sometimes is also responsible for the resistance to some of these treatments.
It is well established that p38 MAPK mediates the responses to several DNA-damaging agents, such as UV radiation, cisplatin (CDDP) and Ara-C through activation of p53-dependent and independent responses (Bulavin et al., 1999; Huang et al., 1997; Sánchez-Prieto et al., 2000). Cisplatin is an anti-cancer drug that induces apoptosis in a number of cancer cell lines through mechanisms that in many cases are p38 dependent. In the colon carcinoma cell line HCT116, the activation of p38α was shown to be necessary for CDDP-induced apoptosis, upon activation by p53-mediated ROS production (Bragado et al., 2007). Once p38α MAPK is activated, it contributes to further activation of p53, which leads to a positive feedback loop. So, a p53/ROS/p38α MAPK cascade is essential for cisplatin-induced cell death and the subsequent p38α/p53 positive feedback loop strongly enhances the initial p53 activation in HCT116 cells. In other cancer cell lines, c-Abl is required for CDDP-induced p38 activation and for its antitumoral effect. Thus, CDDP-induced cell death appears to be dependent on c-Abl expression, rather than on its tyrosine kinase activity, and on stabilization of MKK6 protein levels (Galán-Moya et al., 2008). This pro-apoptotic effect of CDDP is not selective for tumoral cells. Hence, in NIH3T3 cells, which are non-transformed cells, an involvement of p38(α/β) MAPK was described as mediator of CDDP-induced apoptosis through a mechanism dependent on the phosphorylation of p53 in Ser33 and the subsequent p53 transcriptional activation (Sánchez-Prieto et al., 2000).
Similarly to CDDP, other anticancer drugs also lead to the generation of ROS as an important mechanism to induce apoptosis in cancer cells, being p38α a relevant mediator. Thus, diamine, a thiol-oxidizing compound, induces apoptosis in a gastric human adenocarcinoma cell line (AGS) through a mechanism dependent on Trx1/p38α/p53 pathway, while CaCo2 cells are resistant to this compound due to the absence of a functional p53 (Piccirillo et al., 2009).
As previously mentioned, activation of p38 MAPK plays a key role in some hematopoietic malignancies by different mechanisms including increasing resistance to chemotherapeutic agents (Feng et al., 2009). Ara C is a classic anti-neoplasic agent widely used in the treatment of CML blast crisis, which provides a typical example of genotoxic stress mediated through c-Abl-p38 MAPK pathway (Huang et al., 1997; Pandey et al., 1996; Stadheim et al., 2000). Although p38 MAPK is activated by c-Abl in response to CDDP in some cancer cell lines (Galán-Moya et al., 2008) and by overexpression of Bcr-Abl, Ara-C (1-β-D-arabinofuranosylcytosine) is unable to activate p38 MAPK in cells with constitutive expression of Bcr-Abl such as the CML derived cell line K562 (Sánchez-Arévalo Lobo et al., 2005). In those cells, Bcr-Abl induces a sustained activation of the p38 MAPK pathway (not related to increased apoptosis), rendering them insensitive to further activation in response to Ara-C. Therefore, Bcr-Abl mediated p38 MAPK activation is a key mechanism to explain resistance to Ara-C. In fact, lack of p38 MAPK activation is a general mechanism for Ara-C resistance, as it had been previously proposed (Stadheim et al., 2000). This could provide a clue for new therapeutic approaches based on the combined use of specific Abl and p38 MAPK inhibitors.
In contrast, p38 MAPK signaling cascade mediates the antiproliferative effects of STI-571 (or imatinib, the current drug used in CML treatment) and cisplatin on Bcr-Abl expressing cells (Galán-Moya et al., 2008; Parmar et al., 2004). Moreover, we have recently found a functional relationship between C3G and p38 in CML, so that the pro-apoptotic activity of p38α MAPK, as a mediator of STI-571 effects, is downregulated by the C3G-Rap1 pathway and the antitumoral effects of STI-571 could be improved by C3G gene silencing as it enhances p38α activation and pro-apoptotic activity (Maia et al., 2009).
In contrast, p38 appears to be a negative regulator of the antitumoral effects of all-trans-retinoic acid (RA), which induces differentiation and growth arrest in several malignant cell types, including acute promyelocytic leukemia (APL) and breast carcinoma. The Rac-p38 MAPK-MK2 pathway is activated by RA and negatively regulates RA-effects in NB-4 APL and MCF-7 breast cancer cell lines, as p38α/β inhibitor SB203580 enhances RA-dependent cell differentiation and apoptosis. Therefore, pharmacological inhibition of p38α/β may prevent resistance to RA that is developed in nearly all cases (Alsayed et al., 2001).
Arsenic trioxide (AT), which also induces differentiation and apoptosis of leukemia cells in vitro and in vivo, activates the Rac-p38 MAPK-MK2 pathway, which can act as a negative regulator of AT functions, suggesting a possible role of p38 MAPK pathways in AT-induced resistance (Verma et al., 2002b). However, AT can sensitize human promonocytic cells U937 to TNF-α-induced apoptosis, which is dependent on p38α/β activation (Amran et al., 2007). AT increases the levels of TNF-α receptor leading to an enhancement of TNF-α-induced apoptosis.
The role of p38 MAPK in resistance to chemotherapeutic agents is also observed in an experimental model of head and neck cancer, where lower activation or lack of activation of p38 MAPK correlates with a more resistant phenotype (Losa et al., 2003).
Therefore, based on all these data described here and other published data, p38α would play a dual role in cancer treatment. Depending on the type of tumour and the chemotherapeutic agent, p38α can either induce apoptosis or survival, leading to the disappearance of the tumour or making it resistant to chemotherapy.
p38α MAPK (encoded by MAPK14 gene) is broadly expressed and is also the most abundant p38 isoform present in most cell types. It can be activated by several extracellular signals, including stress stimuli, leading to the regulation of different cellular processes, which includes cell death. Although in many cases p38α is a mediator of apoptosis, recent data indicate that it can also have a pro-survival role. Therefore, p38α would play a dual role in apoptosis, which is dependent on the cell context and/or stimulus.
p38α regulates apoptosis through transcriptional and posttranscriptional mechanisms, being of particular relevance the modulation of proteins from the Bcl-2 family and proteins involved in the death receptor pathway such as Fas and FasL.
p38α-mediated apoptosis or survival is deregulated in a number of pathologies. For example, some neurodegenerative diseases are linked to an enhanced apoptosis mediated by p38α. p38α can also act as a tumour suppressor in the initial stages of malignant transformation through activation of apoptosis. In addition, the antitumoral effects of a number of chemotherapeutical drugs are based on the activation of apoptosis through p38α. However, it should be notice that in some tumours p38α MAPK is involved in chemotherapeutical resistance.
We apologize to the authors whose original work is not included in the references due to extension constrains.
|Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27.|
|Freshney NW, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J, Saklatvala J.|
|Cell. 1994 Sep 23;78(6):1039-49.|
|A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells.|
|Han J, Lee JD, Bibbs L, Ulevitch RJ.|
|Science. 1994 Aug 5;265(5173):808-11.|
|A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins.|
|Rouse J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt T, Nebreda AR.|
|Cell. 1994 Sep 23;78(6):1027-37.|
|Rho, rac and cdc42 GTPases: regulators of actin structures, cell adhesion and motility.|
|Nobes CD, Hall A.|
|Biochem Soc Trans. 1995 Aug;23(3):456-9. (REVIEW)|
|Activation of p38 mitogen-activated protein kinase by c-Abl-dependent and -independent mechanisms.|
|Pandey P, Raingeaud J, Kaneki M, Weichselbaum R, Davis RJ, Kufe D, Kharbanda S.|
|J Biol Chem. 1996 Sep 27;271(39):23775-9.|
|Pro-apoptotic effect of the c-Abl tyrosine kinase in the cellular response to 1-beta-D-arabinofuranosylcytosine.|
|Huang Y, Yuan ZM, Ishiko T, Nakada S, Utsugisawa T, Kato T, Kharbanda S, Kufe DW.|
|Oncogene. 1997 Oct 16;15(16):1947-52.|
|Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family.|
|Wang Y, Huang S, Sah VP, Ross J Jr, Brown JH, Han J, Chien KR.|
|J Biol Chem. 1998 Jan 23;273(4):2161-8.|
|Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation.|
|Bulavin DV, Saito S, Hollander MC, Sakaguchi K, Anderson CW, Appella E, Fornace AJ Jr.|
|EMBO J. 1999 Dec 1;18(23):6845-54.|
|p38 mitogen-activated protein kinase is involved in Fas ligand expression.|
|Hsu SC, Gavrilin MA, Tsai MH, Han J, Lai MZ.|
|J Biol Chem. 1999 Sep 3;274(36):25769-76.|
|Withdrawal of survival factors results in activation of the JNK pathway in neuronal cells leading to Fas ligand induction and cell death.|
|Le-Niculescu H, Bonfoco E, Kasuya Y, Claret FX, Green DR, Karin M.|
|Mol Cell Biol. 1999 Jan;19(1):751-63.|
|An inhibitor of p38 mitogen-activated protein kinase protects neonatal cardiac myocytes from ischemia.|
|Mackay K, Mochly-Rosen D.|
|J Biol Chem. 1999 Mar 5;274(10):6272-9.|
|Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development.|
|Adams RH, Porras A, Alonso G, Jones M, Vintersten K, Panelli S, Valladares A, Perez L, Klein R, Nebreda AR.|
|Mol Cell. 2000 Jul;6(1):109-16.|
|The integrin-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3beta and cAMP-responsive element-binding protein-dependent pathways.|
|D'Amico M, Hulit J, Amanatullah DF, Zafonte BT, Albanese C, Bouzahzah B, Fu M, Augenlicht LH, Donehower LA, Takemaru K, Moon RT, Davis R, Lisanti MP, Shtutman M, Zhurinsky J, Ben-Ze'ev A, Troussard AA, Dedhar S, Pestell RG.|
|J Biol Chem. 2000 Oct 20;275(42):32649-57.|
|p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons.|
|Ghatan S, Larner S, Kinoshita Y, Hetman M, Patel L, Xia Z, Youle RJ, Morrison RS.|
|J Cell Biol. 2000 Jul 24;150(2):335-47.|
|p38 protects human melanoma cells from UV-induced apoptosis through down-regulation of NF-kappaB activity and Fas expression.|
|Ivanov VN, Ronai Z.|
|Oncogene. 2000 Jun 15;19(26):3003-12.|
|Essential role for p38alpha mitogen-activated protein kinase in placental angiogenesis.|
|Mudgett JS, Ding J, Guh-Siesel L, Chartrain NA, Yang L, Gopal S, Shen MM.|
|Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10454-9.|
|p38 MAP kinases: beyond the stress response.|
|Nebreda AR, Porras A.|
|Trends Biochem Sci. 2000 Jun;25(6):257-60. (REVIEW)|
|Antiapoptotic role of the p38 mitogen-activated protein kinase-myocyte enhancer factor 2 transcription factor pathway during neuronal differentiation.|
|Okamoto S, Krainc D, Sherman K, Lipton SA.|
|Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7561-6.|
|The p38 signal transduction pathway: activation and function.|
|Ono K, Han J.|
|Cell Signal. 2000 Jan;12(1):1-13. (REVIEW)|
|A role for the p38 mitogen-acitvated protein kinase pathway in the transcriptional activation of p53 on genotoxic stress by chemotherapeutic agents.|
|Sanchez-Prieto R, Rojas JM, Taya Y, Gutkind JS.|
|Cancer Res. 2000 May 1;60(9):2464-72.|
|The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes.|
|Saurin AT, Martin JL, Heads RJ, Foley C, Mockridge JW, Wright MJ, Wang Y, Marber MS.|
|FASEB J. 2000 Nov;14(14):2237-46.|
|Role of c-Jun N-terminal kinase/p38 stress signaling in 1-beta-D-arabinofuranosylcytosine-induced apoptosis.|
|Stadheim TA, Saluta GR, Kucera GL.|
|Biochem Pharmacol. 2000 Feb 15;59(4):407-18.|
|Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis.|
|Tamura K, Sudo T, Senftleben U, Dadak AM, Johnson R, Karin M.|
|Cell. 2000 Jul 21;102(2):221-31.|
|p38 mitogen-activated protein kinase mediates tumor necrosis factor-alpha-induced apoptosis in rat fetal brown adipocytes.|
|Valladares A, Alvarez AM, Ventura JJ, Roncero C, Benito M, Porras A.|
|Endocrinology. 2000 Dec;141(12):4383-95.|
|p38 mitogen-activated protein kinase mediates bid cleavage, mitochondrial dysfunction, and caspase-3 activation during apoptosis induced by singlet oxygen but not by hydrogen peroxide.|
|Zhuang S, Demirs JT, Kochevar IE.|
|J Biol Chem. 2000 Aug 25;275(34):25939-48.|
|Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to all-trans-retinoic acid.|
|Alsayed Y, Uddin S, Mahmud N, Lekmine F, Kalvakolanu DV, Minucci S, Bokoch G, Platanias LC.|
|J Biol Chem. 2001 Feb 9;276(6):4012-9. Epub 2000 Nov 1.|
|Mechanisms underlying neuronal death induced by chromogranin A-activated microglia.|
|Ciesielski-Treska J, Ulrich G, Chasserot-Golaz S, Zwiller J, Revel MO, Aunis D, Bader MF.|
|J Biol Chem. 2001 Apr 20;276(16):13113-20. Epub 2000 Dec 21.|
|Pro-apoptotic gene expression mediated by the p38 mitogen-activated protein kinase signal transduction pathway.|
|De Zutter GS, Davis RJ.|
|Proc Natl Acad Sci U S A. 2001 May 22;98(11):6168-73. Epub 2001 May 8.|
|Involvement of p38 in apoptosis-associated membrane blebbing and nuclear condensation.|
|Deschesnes RG, Huot J, Valerie K, Landry J.|
|Mol Biol Cell. 2001 Jun;12(6):1569-82.|
|Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation.|
|Kyriakis JM, Avruch J.|
|Physiol Rev. 2001 Apr;81(2):807-69. (REVIEW)|
|The p38 MAPK pathway mediates the growth inhibitory effects of interferon-alpha in BCR-ABL-expressing cells.|
|Mayer IA, Verma A, Grumbach IM, Uddin S, Lekmine F, Ravandi F, Majchrzak B, Fujita S, Fish EN, Platanias LC.|
|J Biol Chem. 2001 Jul 27;276(30):28570-7. Epub 2001 May 15.|
|Induction of apoptosis and Fas receptor/Fas ligand expression by ischemia/reperfusion in cardiac myocytes requires serine 727 of the STAT-1 transcription factor but not tyrosine 701.|
|Stephanou A, Scarabelli TM, Brar BK, Nakanishi Y, Matsumura M, Knight RA, Latchman DS.|
|J Biol Chem. 2001 Jul 27;276(30):28340-7. Epub 2001 Apr 17.|
|Nerve growth factor inhibits apoptosis in memory B lymphocytes via inactivation of p38 MAPK, prevention of Bcl-2 phosphorylation, and cytochrome c release.|
|Torcia M, De Chiara G, Nencioni L, Ammendola S, Labardi D, Lucibello M, Rosini P, Marlier LN, Bonini P, Dello Sbarba P, Palamara AT, Zambrano N, Russo T, Garaci E, Cozzolino F.|
|J Biol Chem. 2001 Oct 19;276(42):39027-36. Epub 2001 Aug 8.|
|Insulin-like growth factor I induces MDM2-dependent degradation of p53 via the p38 MAPK pathway in response to DNA damage.|
|Heron-Milhavet L, LeRoith D.|
|J Biol Chem. 2002 May 3;277(18):15600-6. Epub 2002 Feb 27.|
|p38 MAPK-mediated activation of NF-kappaB by the RhoGEF domain of Bcr.|
|Korus M, Mahon GM, Cheng L, Whitehead IP.|
|Oncogene. 2002 Jul 11;21(30):4601-12.|
|Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition.|
|Park JM, Greten FR, Li ZW, Karin M.|
|Science. 2002 Sep 20;297(5589):2048-51. Epub 2002 Aug 29.|
|The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell chronic lymphocytic leukemia cells through a p38 mitogen activated protein-kinase-dependent mechanism.|
|Pedersen IM, Buhl AM, Klausen P, Geisler CH, Jurlander J.|
|Blood. 2002 Feb 15;99(4):1314-9.|
|Activation of the p38 mitogen-activated protein kinase mediates the suppressive effects of type I interferons and transforming growth factor-beta on normal hematopoiesis.|
|Verma A, Deb DK, Sassano A, Uddin S, Varga J, Wickrema A, Platanias LC.|
|J Biol Chem. 2002a Mar 8;277(10):7726-35. Epub 2001 Dec 31.|
|Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide.|
|Verma A, Mohindru M, Deb DK, Sassano A, Kambhampati S, Ravandi F, Minucci S, Kalvakolanu DV, Platanias LC.|
|J Biol Chem. 2002b Nov 22;277(47):44988-95. Epub 2002 Sep 17.|
|Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3.|
|Edlund S, Bu S, Schuster N, Aspenstrom P, Heuchel R, Heldin NE, ten Dijke P, Heldin CH, Landstrom M.|
|Mol Biol Cell. 2003 Feb;14(2):529-44.|
|Role of the p38 MAPK pathway in cisplatin-based therapy.|
|Losa JH, Parada Cobo C, Viniegra JG, Sanchez-Arevalo Lobo VJ, Ramon y Cajal S, Sanchez-Prieto R.|
|Oncogene. 2003 Jun 26;22(26):3998-4006.|
|Map kinase signaling pathways and hematologic malignancies.|
|Blood. 2003 Jun 15;101(12):4667-79. Epub 2003 Mar 6. (REVIEW)|
|H2O2 and 4-hydroxynonenal mediate amyloid beta-induced neuronal apoptosis by activating JNKs and p38MAPK.|
|Tamagno E, Robino G, Obbili A, Bardini P, Aragno M, Parola M, Danni O.|
|Exp Neurol. 2003 Apr;180(2):144-55.|
|Protein kinase C promotes apoptosis in LNCaP prostate cancer cells through activation of p38 MAPK and inhibition of the Akt survival pathway.|
|Tanaka Y, Gavrielides MV, Mitsuuchi Y, Fujii T, Kazanietz MG.|
|J Biol Chem. 2003 Sep 5;278(36):33753-62. Epub 2003 Jun 24.|
|Persistent activation of p38 mitogen-activated protein kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with disease progression.|
|Tortarolo M, Veglianese P, Calvaresi N, Botturi A, Rossi C, Giorgini A, Migheli A, Bendotti C.|
|Mol Cell Neurosci. 2003 Jun;23(2):180-92.|
|Carbon monoxide modulates Fas/Fas ligand, caspases, and Bcl-2 family proteins via the p38alpha mitogen-activated protein kinase pathway during ischemia-reperfusion lung injury.|
|Zhang X, Shan P, Alam J, Davis RJ, Flavell RA, Lee PJ.|
|J Biol Chem. 2003 Jun 13;278(24):22061-70. Epub 2003 Apr 10.|
|Ultraviolet A-induced modulation of Bcl-XL by p38 MAPK in human keratinocytes: post-transcriptional regulation through the 3'-untranslated region.|
|Bachelor MA, Bowden GT.|
|J Biol Chem. 2004 Oct 8;279(41):42658-68. Epub 2004 Aug 2.|
|Activated p38MAPK is a novel component of the intracellular inclusions found in human amyotrophic lateral sclerosis and mutant SOD1 transgenic mice.|
|Bendotti C, Atzori C, Piva R, Tortarolo M, Strong MJ, DeBiasi S, Migheli A.|
|J Neuropathol Exp Neurol. 2004 Feb;63(2):113-9.|
|Inhibition of mixed lineage kinase 3 attenuates MPP+-induced neurotoxicity in SH-SY5Y cells.|
|Mathiasen JR, McKenna BA, Saporito MS, Ghadge GD, Roos RP, Holskin BP, Wu ZL, Trusko SP, Connors TC, Maroney AC, Thomas BA, Thomas JC, Bozyczko-Coyne D.|
|Brain Res. 2004 Apr 2;1003(1-2):86-97.|
|Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells.|
|Parmar S, Katsoulidis E, Verma A, Li Y, Sassano A, Lal L, Majchrzak B, Ravandi F, Tallman MS, Fish EN, Platanias LC.|
|J Biol Chem. 2004 Jun 11;279(24):25345-52. Epub 2004 Mar 31.|
|P38 alpha mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli.|
|Porras A, Zuluaga S, Black E, Valladares A, Alvarez AM, Ambrosino C, Benito M, Nebreda AR.|
|Mol Biol Cell. 2004 Feb;15(2):922-33. Epub 2003 Nov 14.|
|Expression of stress-activated kinases c-Jun N-terminal kinase (SAPK/JNK-P) and p38 kinase (p38-P), and tau hyperphosphorylation in neurites surrounding betaA plaques in APP Tg2576 mice.|
|Puig B, Gomez-Isla T, Ribe E, Cuadrado M, Torrejon-Escribano B, Dalfo E, Ferrer I.|
|Neuropathol Appl Neurobiol. 2004 Oct;30(5):491-502.|
|p38alpha, but not p38beta, inhibits the phosphorylation and presence of c-FLIPS in DISC to potentiate Fas-mediated caspase-8 activation and type I apoptotic signaling.|
|Tourian L Jr, Zhao H, Srikant CB.|
|J Cell Sci. 2004 Dec 15;117(Pt 26):6459-71. Epub 2004 Nov 30.|
|Differentiation stage-specific activation of p38 mitogen-activated protein kinase isoforms in primary human erythroid cells.|
|Uddin S, Ah-Kang J, Ulaszek J, Mahmud D, Wickrema A.|
|Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):147-52. Epub 2003 Dec 23.|
|Sustained activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase pathways by hepatitis B virus X protein mediates apoptosis via induction of Fas/FasL and tumor necrosis factor (TNF) receptor 1/TNF-alpha expression.|
|Wang WH, Gregori G, Hullinger RL, Andrisani OM.|
|Mol Cell Biol. 2004 Dec;24(23):10352-65.|
|Inter- and intracellular signaling in amyotrophic lateral sclerosis: role of p38 mitogen-activated protein kinase.|
|Bendotti C, Bao Cutrona M, Cheroni C, Grignaschi G, Lo Coco D, Peviani M, Tortarolo M, Veglianese P, Zennaro E.|
|Neurodegener Dis. 2005;2(3-4):128-34. (REVIEW)|
|Molecular pathogenesis of Parkinson's disease.|
|Gandhi S, Wood NW.|
|Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:2749-2755. (REVIEW)|
|Phorbol ester-induced apoptosis in prostate cancer cells via autocrine activation of the extrinsic apoptotic cascade: a key role for protein kinase C delta.|
|Gonzalez-Guerrico AM, Kazanietz MG.|
|J Biol Chem. 2005 Nov 25;280(47):38982-91. Epub 2005 Sep 23.|
|Activation of the stress-activated MAP kinase, p38, but not JNK in cortical motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in transgenic mice.|
|Holasek SS, Wengenack TM, Kandimalla KK, Montano C, Gregor DM, Curran GL, Poduslo JF.|
|Brain Res. 2005 May 31;1045(1-2):185-98. Epub 2005 Apr 25.|
|Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope.|
|Perfettini JL, Castedo M, Nardacci R, Ciccosanti F, Boya P, Roumier T, Larochette N, Piacentini M, Kroemer G.|
|J Exp Med. 2005 Jan 17;201(2):279-89. Epub 2005 Jan 10.|
|Protein kinase C delta induces apoptosis of vascular smooth muscle cells through induction of the tumor suppressor p53 by both p38-dependent and p38-independent mechanisms.|
|Ryer EJ, Sakakibara K, Wang C, Sarkar D, Fisher PB, Faries PL, Kent KC, Liu B.|
|J Biol Chem. 2005 Oct 21;280(42):35310-7. Epub 2005 Aug 23.|
|Modulation of the p38 MAPK (mitogen-activated protein kinase) pathway through Bcr/Abl: implications in the cellular response to Ara-C.|
|Sanchez-Arevalo Lobo VJ, Aceves Luquero CI, Alvarez-Vallina L, Tipping AJ, Viniegra JG, Hernandez Losa J, Parada Cobo C, Galan Moya EM, Gayoso Cruz J, Melo JV, Ramon y Cajal S, Sanchez-Prieto R.|
|Biochem J. 2005 Apr 1;387(Pt 1):231-8.|
|Mixed lineage kinase-c-jun N-terminal kinase signaling pathway: a new therapeutic target in Parkinson's disease.|
|Silva RM, Kuan CY, Rakic P, Burke RE.|
|Mov Disord. 2005 Jun;20(6):653-64. (REVIEW)|
|p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65.|
|Cai B, Chang SH, Becker EB, Bonni A, Xia Z.|
|J Biol Chem. 2006 Sep 1;281(35):25215-22. Epub 2006 Jul 3.|
|Bax translocates to mitochondria of heart cells during simulated ischaemia: involvement of AMP-activated and p38 mitogen-activated protein kinases.|
|Capano M, Crompton M.|
|Biochem J. 2006 Apr 1;395(1):57-64.|
|Altered cell adhesion and cell viability in a p38alpha mitogen-activated protein kinase-deficient mouse embryonic stem cell line.|
|Guo YL, Yang B.|
|Stem Cells Dev. 2006 Oct;15(5):655-64.|
|JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells.|
|Kim BJ, Ryu SW, Song BJ.|
|J Biol Chem. 2006 Jul 28;281(30):21256-65. Epub 2006 May 18.|
|Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors.|
|Navas TA, Mohindru M, Estes M, Ma JY, Sokol L, Pahanish P, Parmar S, Haghnazari E, Zhou L, Collins R, Kerr I, Nguyen AN, Xu Y, Platanias LC, List AA, Higgins LS, Verma A.|
|Blood. 2006 Dec 15;108(13):4170-7. Epub 2006 Aug 29.|
|Models, mechanisms and clinical evidence for cancer dormancy.|
|Nat Rev Cancer. 2007 Nov;7(11):834-46. (REVIEW)|
|Arsenic trioxide sensitizes promonocytic leukemia cells to TNFalpha-induced apoptosis via p38-MAPK-regulated activation of both receptor-mediated and mitochondrial pathways.|
|Amran D, Sanchez Y, Fernandez C, Ramos AM, de Blas E, Breard J, Calle C, Aller P.|
|Biochim Biophys Acta. 2007 Nov;1773(11):1653-63. Epub 2007 Jun 22.|
|Apoptosis by cisplatin requires p53 mediated p38alpha MAPK activation through ROS generation.|
|Bragado P, Armesilla A, Silva A, Porras A.|
|Apoptosis. 2007 Sep;12(9):1733-42.|
|A novel cell type-specific role of p38alpha in the control of autophagy and cell death in colorectal cancer cells.|
|Comes F, Matrone A, Lastella P, Nico B, Susca FC, Bagnulo R, Ingravallo G, Modica S, Lo Sasso G, Moschetta A, Guanti G, Simone C.|
|Cell Death Differ. 2007 Apr;14(4):693-702. Epub 2006 Dec 8.|
|A new p38 MAP kinase-regulated transcriptional coactivator that stimulates p53-dependent apoptosis.|
|Cuadrado A, Lafarga V, Cheung PC, Dolado I, Llanos S, Cohen P, Nebreda AR.|
|EMBO J. 2007 Apr 18;26(8):2115-26. Epub 2007 Mar 22.|
|p38 MAP-kinases pathway regulation, function and role in human diseases.|
|Cuenda A, Rousseau S.|
|Biochim Biophys Acta. 2007 Aug;1773(8):1358-75. Epub 2007 Mar 24. (REVIEW)|
|Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1(G93A)-induced motor neuron death.|
|Dewil M, dela Cruz VF, Van Den Bosch L, Robberecht W.|
|Neurobiol Dis. 2007 May;26(2):332-41. Epub 2007 Feb 6.|
|p38alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis.|
|Dolado I, Swat A, Ajenjo N, De Vita G, Cuadrado A, Nebreda AR.|
|Cancer Cell. 2007 Feb;11(2):191-205.|
|Interaction of ASK1 and the beta-amyloid precursor protein in a stress-signaling complex.|
|Galvan V, Banwait S, Spilman P, Gorostiza OF, Peel A, Ataie M, Crippen D, Huang W, Sidhu G, Ichijo H, Bredesen DE.|
|Neurobiol Dis. 2007 Oct;28(1):65-75. Epub 2007 Jul 3.|
|One hundred years after the discovery of Alzheimer's disease. A turning point for therapy?|
|Giacobini E, Becker RE.|
|J Alzheimers Dis. 2007 Aug;12(1):37-52. (REVIEW)|
|Apoptosis and erythroid differentiation triggered by Bcr-Abl inhibitors in CML cell lines are fully distinguishable processes that exhibit different sensitivity to caspase inhibition.|
|Jacquel A, Colosetti P, Grosso S, Belhacene N, Puissant A, Marchetti S, Breittmayer JP, Auberger P.|
|Oncogene. 2007 Apr 12;26(17):2445-58. Epub 2006 Oct 9.|
|ERK1/2 inactivation and p38 MAPK-dependent caspase activation during guanosine 5'-triphosphate-mediated terminal erythroid differentiation of K562 cells.|
|Moosavi MA, Yazdanparast R, Lotfi A.|
|Int J Biochem Cell Biol. 2007;39(9):1685-97. Epub 2007 May 4.|
|p38 MAP kinase regulates stem cell apoptosis in human hematopoietic failure.|
|Zhou L, Opalinska J, Verma A.|
|Cell Cycle. 2007 Mar 1;6(5):534-7. Epub 2007 Mar 25. (REVIEW)|
|Negative regulation of Akt activity by p38alpha MAP kinase in cardiomyocytes involves membrane localization of PP2A through interaction with caveolin-1.|
|Zuluaga S, Alvarez-Barrientos A, Gutierrez-Uzquiza A, Benito M, Nebreda AR, Porras A.|
|Cell Signal. 2007a Jan;19(1):62-74. Epub 2006 Jul 14.|
|p38alpha MAPK can positively or negatively regulate Rac-1 activity depending on the presence of serum.|
|Zuluaga S, Gutierrez-Uzquiza A, Bragado P, Alvarez-Barrientos A, Benito M, Nebreda AR, Porras A.|
|FEBS Lett. 2007b Aug 7;581(20):3819-25. Epub 2007 Jul 16.|
|p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription.|
|Cai B, Xia Z.|
|Apoptosis. 2008 Jun;13(6):803-10.|
|c-Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin-based therapy.|
|Galan-Moya EM, Hernandez-Losa J, Aceves Luquero CI, de la Cruz-Morcillo MA, Ramirez-Castillejo C, Callejas-Valera JL, Arriaga A, Aranburo AF, Ramon y Cajal S, Silvio Gutkind J, Sanchez-Prieto R.|
|Int J Cancer. 2008 Jan 15;122(2):289-97.|
|Epidermal growth factor abrogates hypoxia-induced apoptosis in cultured human trophoblasts through phosphorylation of BAD Serine 112.|
|Humphrey RG, Sonnenberg-Hirche C, Smith SD, Hu C, Barton A, Sadovsky Y, Nelson DM.|
|Endocrinology. 2008 May;149(5):2131-7. Epub 2008 Feb 14.|
|Selective activation of p38 mitogen-activated protein kinase in dopaminergic neurons of substantia nigra leads to nuclear translocation of p53 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice.|
|Karunakaran S, Saeed U, Mishra M, Valli RK, Joshi SD, Meka DP, Seth P, Ravindranath V.|
|J Neurosci. 2008 Nov 19;28(47):12500-9.|
|Alpha-synuclein activates stress signaling protein kinases in THP-1 cells and microglia.|
|Klegeris A, Pelech S, Giasson BI, Maguire J, Zhang H, McGeer EG, McGeer PL.|
|Neurobiol Aging. 2008 May;29(5):739-52. Epub 2006 Dec 12.|
|Serum starvation induces H2AX phosphorylation to regulate apoptosis via p38 MAPK pathway.|
|Lu C, Shi Y, Wang Z, Song Z, Zhu M, Cai Q, Chen T.|
|FEBS Lett. 2008 Aug 6;582(18):2703-8. Epub 2008 Jul 9.|
|ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo.|
|Schewe DM, Aguirre-Ghiso JA.|
|Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10519-24. Epub 2008 Jul 23.|
|p38 Mitogen-activated protein kinase and hematologic malignancies.|
|Feng Y, Wen J, Chang CC.|
|Arch Pathol Lab Med. 2009 Nov;133(11):1850-6. (REVIEW)|
|C3G silencing enhances STI-571-induced apoptosis in CML cells through p38 MAPK activation, but it antagonizes STI-571 inhibitory effect on survival.|
|Maia V, Sanz M, Gutierrez-Berzal J, de Luis A, Gutierrez-Uzquiza A, Porras A, Guerrero C.|
|Cell Signal. 2009 Jul;21(7):1229-35. Epub 2009 Mar 24.|
|Regulation of Bcl-2 phosphorylation in response to oxidative stress in cardiac myocytes.|
|Markou T, Dowling AA, Kelly T, Lazou A.|
|Free Radic Res. 2009 Sep;43(9):809-16. Epub 2009 Jun 30.|
|Apoptosis commitment and activation of mitochondrial Bax during anoikis is regulated by p38MAPK.|
|Owens TW, Valentijn AJ, Upton JP, Keeble J, Zhang L, Lindsay J, Zouq NK, Gilmore AP.|
|Cell Death Differ. 2009 Nov;16(11):1551-62. Epub 2009 Aug 7.|
|Redox mechanisms involved in the selective activation of Nrf2-mediated resistance versus p53-dependent apoptosis in adenocarcinoma cells.|
|Piccirillo S, Filomeni G, Brune B, Rotilio G, Ciriolo MR.|
|J Biol Chem. 2009 Oct 2;284(40):27721-33. Epub 2009 Jul 30.|
|Signal integration by JNK and p38 MAPK pathways in cancer development.|
|Wagner EF, Nebreda AR.|
|Nat Rev Cancer. 2009 Aug;9(8):537-49. (REVIEW)|
|C3G down-regulates p38 MAPK activity in response to stress by Rap-1 independent mechanisms: involvement in cell death.|
|Gutierrez-Uzquiza A, Arechederra M, Molina I, Banos R, Maia V, Benito M, Guerrero C, Porras A.|
|Cell Signal. 2010 Mar;22(3):533-42.|
|Pathological roles of MAPK signaling pathways in human diseases.|
|Kim EK, Choi EJ.|
|Biochim Biophys Acta. 2010 Apr;1802(4):396-405. Epub 2010 Jan 14. (REVIEW)|
|Written||2010-06||Almudena Porras, Carmen Guerrero|
|de Bioquímica y Biología Molecular II, Facultad de Farmacia, UCM, Ciudad Universitaria, 28040 Madrid, Spain (AP); Centro de Investigación del Cáncer, IBMCC, Universidad de Salamanca-CSIC, 37007 Salamanca, Spain (CG)|
|This paper should be referenced as such :|
|Porras, A ; Guerrero, C|
|Role of p38α in apoptosis: implication in cancer development, therapy|
|Atlas Genet Cytogenet Oncol Haematol. 2011;15(3):316-326.|
|Free journal version : [ pdf ] [ DOI ]|
|On line version : http://AtlasGeneticsOncology.org/Deep/MAPK14-p38ainCancerID20089.htm|
|© Atlas of Genetics and Cytogenetics in Oncology and Haematology||indexed on : Thu Feb 14 18:19:04 CET 2019|
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