6p21.31

AIG6,FKBP51,FKBP54,P54,PPIase,Ptg-10

Cancer and response to chemotherapy

FKBP51 is an important protein involved in the regulation of many key signaling cascades in the cell, such as Akt (Pei et al., 2009), NFκB (Bouwmeester et al., 2004), and androgen receptor pathways (Ni et al., 2010). All of these signalling pathways are implicated in tumorigenesis and response to drug treatment. It has been suggested that the contribution of FKBP5 in tumorgenesis and antineoplastic therapy is tissue-specific. Depending on the cellular context, FKBP5 can either promote or inhibit tumor progression and chemoresistance.

Pancreatic cancer

The Akt pathway is one of the most important signaling pathways, playing a role in regulation of many cellular processes, including cell proliferation, growth, and other processes that crucial for cell survival (Manning and Cantley, 2007). Akt is a serine/threonine kinase that in order to become fully activated needs its residues: Ser473 and Thr308 to be phosphorylated. This is facilitated by phosphoinositide 3-kinase (PIP3), as well as PDK1, and mTOR complex 2 (Alessi et al., 1996; Engelman et al., 2006; Sarbassov et al., 2005). Conversely, phosphatases, such as PP2 holoenzymes and PHLPP de-phosphorylate Akt, halting its activity (Brognard et al., 2007; Carracedo and Pandolfi, 2008; Gao et al., 2005; Padmanabhan et al., 2009). The balance in phosphorylation levels of Akt determines its pathway activity, therefore affecting all the downstream cellular events. If Akt pathway becomes highly up-regulated, it potentially could lead to tumor development, progression and eventually to chemotherapy resistance (Pei et al., 2010). Genome-wide association studies of cytidine analogues identified FKBP5 low expression levels to be associated with resistance to many chemotherapeutic drugs (Li et al., 2008; Pei et al., 2009). Functional studies of FKBP5 demonstrated that FKBP51 acts as a scaffolding protein increasing interaction between Akts phosphatase - PHLPP and Akt, thus decreasing the phosphorylation of Akt-Ser473 (Pei et al., 2009). It was shown, that in pancreatic and breast cancer cells FKBP5 expression levels are decreased, while the phosphorylation of Akt-Ser473 is increased, which could lead to chemoresistance. Also, it suggested that FKBP5 might function as a tumor suppressor gene through the down-regulation of Akt activation (Pei et al., 2009, Hou and Wang, 2012).

Acute lymphoblastic leukemia, glioma, melanoma

FKBP5 plays a pivotal role in regulating NF-κB pathway (Bouwmeester et al., 2004). Specifically, FKBP51 interacts with several members of the NF-κB pathway including inhibitors of NF-κB kinase: IKKα, IKKε, TAK1 and MEKK1. It was shown, that FKBP51 enzymatic activity is required for IKK activation, which suggested that FKBP5 plays an important role in this pathway. Avellino et al. demonstrated, that the addition of rapamycin, a known inhibitor of FKBP51 enzymatic (PPIase) activity, to anthracycline treatment of blasts from chronic childhood acute lymphoblastic leukemia (ALL) patients would sensitize these cells to anthracyclines (Avellino et al., 2005). These experiments suggested that the combination treatment of rapamycin and doxorubicin inhibits the activation of the NF-κB pathway, which leads to an increase in apoptosis, and, in turn, an increase in sensitivity to chemotherapy (Avellino et al., 2005). Since NF-κB pathway activation leads to anti-apoptotic signals, therefore, in this case, FKBP5 plays a role in chemoresistance to drugs such as anthracyclines. In addition, in glioma cells, FKBP5 expression contributes to glioma cells growth and sensitivity to rapamycin through regulation of the NF-κB pathway (Jiang et al., 2008). FKBP5 was also described to influence radioresistance in melanoma cells (Romano et al., 2010). Specifically, it was found that in melanoma samples FKBP51 controlled radioresistance through the activation of NF-κB pathway, and by silencing expression of FKBP5 in tumors in vitro and in vivo, it contributed to an increase in apoptosis after irradiation.

Prostate cancer

FKBP5 influences androgen receptor signaling in prostate cancer. Androgen receptor (AR) is a transcription factor, regulating expression of multiple genes, including FKBP5 (Makkonen et al., 2009). Additionally, FKBP5 is a part of a positive feedback loop that not only is having its expression regulated by AR and androgen binding, but it also facilitates androgen-dependent transcription. Ni et al. (Ni et al., 2010) reported that FKBP5 forms a superchaperone complex with ATP-bound Hsp90 and p23 that increases binding of androgen to its receptor. This allows for androgen-dependent gene transcription activation and promotes cell growth, which is especially important during prostate cancer progression to the androgen-independent state during disease progression and tumor growth (Ni et al., 2010).

Depression, post-traumatic stress disorder

It has been established that one of the major functions of FKBP51 is to co-chaperone with HSP family members steroid receptors: glucocorticoid (GR) (Denny et al., 2000), progesterone (PR) (Barent et al., 1998), and androgen (AR) (Ni et al., 2010). In addition, FKBP5 intronic regions contain hormone response elements (HRE) that upon GR, PR, or AR activation bind their respective hormones. That, in turn, induces the FKBP5 gene transcription (Hubler et al., 2003; Hubler and Scammell, 2004; Makkonen et al., 2009; Paakinaho et al., 2010) leading to increases in the amount of FKBP51 protein in the cell. FKBP5 modulates steroid hormones binding affinity; therefore it affects their signaling pathways. For example FKBP51 plays an important role in regulating the activity of the glucocorticoid receptor (Davies et al., 2005). When FKBP51 is bound to the GR-complex, the receptor has lower affinity for glucocorticoids, which causes an increase of glucocorticoids in the intercellular environment. On the other hand, once glucocorticoid is bound, FKBP51 dissociate from the complex and is exchanged with FKBP52. That allows for the translocation of GR into the nucleus and interaction with DNA. Once, in the nucleus GR acts as a transcription factor and by binding to glucocorticoid receptor response elements (GRE) of FKBP5 increases its transcription. That leads to increased concentrations of FKBP51 that contribute to higher GR resistance, completing a negative feedback loop on GR sensitivity (Binder, 2009). Since GR plays a role in regulating a stress response, if FKBP5 expression is altered, it could potentially contribute to development of mood disorders, such as depression or post-traumatic stress disorder (Binder, 2009; Binder et al., 2008; Binder et al., 2004).