PIM1 (pim-1 oncogene)

2013-04-01   Sai-Ching Jim Yeung 

The University of Texas M. D. Anderson Cancer Center, Department of General Internal Medicine, Ambulatory Treatment, Emergency Care, Department of Endocrine Neoplasia, Hormonal Disorders, 1515 Holcombe Boulevard, Unit 437, Houston, Texas 77030, USA





PIM1 is a single gene with 5 introns and 6 exons that span 5 kb of DNA in the human genome (Meeker et al., 1987). The gene starts at 37137922 and ends at 37143204 base pairs from pter. It is highly conserved evolutionarily across species.


The mRNA sequence is 2,6 kb in length with a 941 bp coding region.



Size: 313 amino acids; molecular weight: 36 kDa.
The PIM1 gene has six exons, but there are two isoforms of PIM1 protein, 34 kDa and 44 kDa, due to protein synthesis using alternative sites of translation initiation (Saris et al., 1991). Both proteins show comparable kinase activities in vitro, but the 44 kDa isoform contains an N-terminal proline-rich motif that binds the ETK SH3 domain, and is recruited to the plasma membrane (Xie et al., 2006).


The kinase activity of all the PIM proteins is constitutively active, and there are no regulatory domains in the amino acid sequences of the PIM proteins. Thus, unlike other kinases that are regulated by phosphorylation or binding to the plasma membrane, the activity of PIM1 is regulated primarily by transcription, translation and proteosomal degradation (Amaravadi and Thompson, 2005). The gene expression of PIM1 is increased by various cytokines, mitogens and hormones such as G-CSF, GM-CSF, erythropoietin, interleukins, Con A, PMA, interferons, and prolactin (Wang et al., 2001; Hogan et al., 2008; White, 2003). These factors act through the JAK/STAT pathway. The upregulation of PIM1 gene expression results from the binding site of STAT3 or STAT5 to the PIM1 gene promoter, and the ISFR/GAS-sequence (IFN-γ activation sequence) is an important binding site (Block et al., 2012; Matikainen et al., 1999; Yip-Schneider et al., 1995). PIM1 phosphorylates and stabilizes SOCS proteins (suppressor of cytokine signaling) to provide negative feedback regulation of the JAK/STAT pathway (Peltola et al., 2004).
NF-κB, as a downstream transcription factors, could also activate PIM1. In solid tumors, hypoxia would induce the PIM1 expression, independently of HIF1α and by Krueppel-like factor 5 (KLF5) upon DNA damage (Chen et al., 2009a). ERG, as a transcription factors, also plays a role in PIM1 expression in the initial stages of prostate carcinogenesis (Magistroni et al., 2011).
Because of multiple copies of AUUU(A) motifs in the 3UTR and GC-rich regions in the 5UTR, mRNA of PIM genes are short lived (Wang et al., 2005). Translation of PIM1 seems to be cap-dependent, and overexpression of elF4E would increase PIM1 protein level (Hoover et al., 1997). PIM RNA transcripts are regulatory targets of different miRNAs such as microRNAs miR1, miR-210, miR-33a, and miR328, implicating another layer of PIM expression regulation (Eiring et al., 2010; Huang et al., 2009; Nasser et al., 2008; Thomas et al., 2012).
At the post-translational level, the short half-life of PIM1 is primarily regulated by proteasomal degradation. PIM1 protein can be stabilized by the binding to HSP90 (Mizuno et al., 2001). On the other hand, binding to HSP70 would induce the ubiquitylation of PIM1 and proteasomal degradation (Shay et al., 2005). Also, in hypoxia, ubiquitin-mediated proteasomal degradation of PIM is prevented by HSP90 (Mizuno et al., 2001). PIM1 protein stability is further regulated by its phosphorylation status. PIM1 is able to autophosphorylate (Bullock et al., 2005). Phosphorylation by itself and/or other unknown kinases is important for PIM1 protein stability and function because PP2A phosphatase negatively regulates PIM1 stability (Losman et al., 2003).


PIM1 is highly expressed in lymphoid and hematopoietic tissues (bone marrow, thymus, spleen, and fetal liver) (Eichmann et al., 2000) as well as in some non-hematopoietic tissues (e.g., hippocampus, oral epithelium, and the prostate gland). In some myeloid and lymphoid leukemia cell lines, prostate cancer cell lines, and also HeLa cells, PIM have also been detected. The PIM1 protein can be detected subcellularly in the cytoplasm and the nucleus.


PIM1 phosphorylates a large subset of cellular substrates and thus regulates many different cellular processes such as cell cycle progression, cellular division, differentiation and apoptosis.
One of the cell-cycle-related targets of PIM1 is p21waf1 (Wang et al., 2002; Zhang et al., 2007). By phosphorylating the CDK inhibitor p21waf1 on T145, PIM1 lead to the nuclear export and inactivation of p21waf1. Phosphorylation of another CDK inhibitor p27Kip1 at Thr157 and Thr198 would induce its proteasomal degradation and cell cycle progression. Moreover, PIM1 seems to phosphorylate and inactivate the transcription factors of p27Kip1, FoxO1a and FoxO3a (Morishita et al., 2008). Another mechanism of p27Kip1 regulation is the phosphorylation of SKP2 at Thr417, which control its stability and ability to degrade p27 (Cen et al., 2010). Additionally, the phosphorylation of Cdc25A and Cdc25C would induce G1/S and G2/M transition, respectively (Bachmann et al., 2004). PIM1 also implicate in mitosis promotion by interacts with dynein/dynactin and HP1β (Magnuson et al., 2010).
Moreover, PIM1 is involved in genomic instability. By interaction with NuMA (nuclear mitotic apparatus protein), overexpression of PIM1 causes the loss of checkpoint control (Bhattacharya et al., 2002). Consequently, cells with abnormal mitotic spindles are not arrested in mitosis, producing polyploid and multinucleated daughter cells.
PIM1 can also act as an oncogenic survival factor because of its function in blocking apoptotic cell death. It is consensus that phosphorylation of BAD at S112 would induce its proteasomal degradation and thus shifts the apoptosis threshold (Peltola et al., 2004). The proapoptotic activity of ASK1 and PRAS40 would also be impaired by PIM1 phosphorylation (Gu et al., 2009; Zhang et al., 2009). Through inactivation of ASK1 and subsequently less phosphorylation of the stress kinases JNK and p38, caspase-3 activation would be less and thus reduce cell death. Moreover, the block of MDM2 and p53 degradation by PIM1 may induce senescence in embryonic fibroblasts and cancer cells (Hogan et al., 2008).
When bound to MYC at the E-box, PIM1 would participate in the complexs phosphorylation of histone H3 at S10 and thus participate in the stimulation of transcription of a specific subset of MYC-dependent genes (Zippo et al., 2007).
Additionally, PIM1 influences the activity of a number of transcriptional regulators, such as HP-1, PAP-1, TFAF2/SNX6, NFATc1, p100, RUNX, SOCS1, RelA/p65 and c-Myb (Bhattacharya et al., 2002; Evans and Fox, 2007; Ishibashi et al., 2001; Kim et al., 2010; Rainio et al., 2002; Winn et al., 2003).
PIM kinases also phosphorylate 4E-BP1, inhibiting its binding to elF-4E. Since elF-4E is a rate-limiting factor in protein synthesis, PIM kinases may also regulate 5 cap-dependent translation (Beharry et al., 2011).

Implicated in

Entity name
t(3;6)(q27;p21.2) in diffuse large B-cell lymphoma (DLCL); chimeric BCL6 /PIM1
Only 1 case to date.
Hybrid gene
5 PIM1 fused to 3 BCL6; the substitution of the promoter of BCL6 causes deregulation of BCL6.
Entity name
Myeloid and lymphoid leukemias and other lymphomas
PIM1 induces anti-apoptotic oncogenes such as BCR/ABL, FLT2, CBL or JAK2 (Adam et al., 2006; Mizuki et al., 2003; Naramura et al., 2011; Nieborowska-Skorska et al., 2002; Wernig et al., 2008). PIM1 mRNA is upregulated in acute myeloid leukemia (AML) along with MLL gene rearrangements, e.g., MLL/AF9 or MLL/ENL (Chen et al., 2008). The reason for PIM1 levels increase seems to be the constitutive activation of FLT3 or Hoxa9 (Hu et al., 2007). Additionally, PIM1 also involve in the several B-cell developmental disorders that are related to Kaposi sarcoma associated herpesvirus (KSHV) or the Epstein-Barr virus (EBV) (Bajaj et al., 2006; Cheng et al., 2009).
Entity name
Prostate cancer
In more half of the prostate cancer samples, PIM1 is showed a relatively overexpression compared to benign lesions and the expression elevation correlated with a poor therapeutic outcome (Dhanasekaran et al., 2001).
In mouse model, the synergistic effects of PIM1 and MYC showed obvious co-regulation in prostate cancer. The molecular mechanism for the oncogenic activity might because PIM1 phosphorylation of c-MYC would increase its half-life and also because PIM1 enhancement of transcriptional activity of c-MYC (Chen et al., 2009b; Mumenthaler et al., 2009). Moreover, PIM1 kinase is related to chemoresistance in prostate cancer cells, which is related to relatively aggressive or hormone-refractory prostate cancers. The high level of expression of PIM1 in high grade prostate intraepithelial neoplasia may indicate a role of PIM1 in the early prostate carcinogenesis. PIM1 is also found to be upregulated in patients undergoing androgen ablation therapy (van der Poel et al., 2010).
Entity name
Pancreatic cancer
Hypoxia-promoted genetic instability
PIM1 increases in hypoxic condition, independently of HIF-1α (Reiser-Erkan et al., 2008). It is now proposed as a prognostic marker. Increase in PIM1 expression may partly account for resistance to chemotherapy.
Entity name
Sporadic malignant tumors
Overexpression of PIM1 is founded in gastric carcinoma, squamous cell carcinoma, colorectal carcinoma, liver carcinoma (Shah et al., 2008), liposarcoma (Nga et al., 2010), and bladder cancer (Guo et al., 2010).


Pubmed IDLast YearTitleAuthors
165852102006Targeting PIM kinases impairs survival of hematopoietic cells transformed by kinase inhibitor-sensitive and kinase inhibitor-resistant forms of Fms-like tyrosine kinase 3 and BCR/ABL.Adam M et al
162001942005The survival kinases Akt and Pim as potential pharmacological targets.Amaravadi R et al
153194452004The oncogenic serine/threonine kinase Pim-1 phosphorylates and inhibits the activity of Cdc25C-associated kinase 1 (C-TAK1): a novel role for Pim-1 at the G2/M cell cycle checkpoint.Bachmann M et al
166470972006KSHV encoded LANA upregulates Pim-1 and is a substrate for its kinase activity.Bajaj BG et al
211874262011The Pim protein kinases regulate energy metabolism and cell growth.Beharry Z et al
121113312002Pim-1 associates with protein complexes necessary for mitosis.Bhattacharya N et al
222736982012IL-6 stimulates STAT3 and Pim-1 kinase in pancreatic cancer cell lines.Block KM et al
163028002005Structural basis of inhibitor specificity of the human protooncogene proviral insertion site in moloney murine leukemia virus (PIM-1) kinase.Bullock AN et al
206638732010Regulation of Skp2 levels by the Pim-1 protein kinase.Cen B et al
194837292009Pim-1 plays a pivotal role in hypoxia-induced chemoresistance.Chen J et al
184551262008Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells.Chen W et al
192660832009KSHV reactivation from latency requires Pim-1 and Pim-3 kinases to inactivate the latency-associated nuclear antigen LANA.Cheng F et al
115189672001Delineation of prognostic biomarkers in prostate cancer.Dhanasekaran SM et al
107137102000Developmental expression of pim kinases suggests functions also outside of the hematopoietic system.Eichmann A et al
202111352010miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts.Eiring AM et al
172392412007Interleukin-10 inhibits osteoclastogenesis by reducing NFATc1 expression and preventing its translocation to the nucleus.Evans KE et al
197497992009PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis.Gu JJ et al
211439892010Overexpression of Pim-1 in bladder cancer.Guo S et al
184673332008Elevated levels of oncogenic protein kinase Pim-1 induce the p53 pathway in cultured cells and correlate with increased Mdm2 in mantle cell lymphoma.Hogan C et al
94194251997Pim-1 protein expression is regulated by its 5'-untranslated region and translation initiation factor elF-4E.Hoover DS et al
173274002007Evidence that the Pim1 kinase gene is a direct target of HOXA9.Hu YL et al
197820342009Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation.Huang X et al
115913662001Pim-1 translocates sorting nexin 6/TRAF4-associated factor 2 from cytoplasm to nucleus.Ishibashi Y et al
210684072010Pim-1 regulates RANKL-induced osteoclastogenesis via NF-κB activation and NFATc1 induction.Kim K et al
149815362004Synergism of cytoplasmic kinases in IL6-induced ligand-independent activation of androgen receptor in prostate cancer cells.Kim O et al
106644482000Identification of heterochromatin protein 1 (HP1) as a phosphorylation target by Pim-1 kinase and the effect of phosphorylation on the transcriptional repression function of HP1(1).Koike N et al
98090631998Pim-1 kinase and p100 cooperate to enhance c-Myb activity.Leverson JD et al
124736742003Protein phosphatase 2A regulates the stability of Pim protein kinases.Losman JA et al
221405322011ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells.Magistroni V et al
209198292010Why target PIM1 for cancer diagnosis and treatment?Magnuson NS et al
100686711999Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2Ralpha, c-myc, and pim-1 genes in human T cells.Matikainen S et al
34294891987Cloning and characterization of the human PIM-1 gene: a putative oncogene related to the protein kinases.Meeker TC et al
124684332003Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations.Mizuki M et al
112377092001Regulation of Pim-1 by Hsp90.Mizuno K et al
103734781999Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway.Mochizuki T et al
185939062008Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels.Morishita D et al
198258062009Pharmacologic inhibition of Pim kinases alters prostate cancer cell growth and resensitizes chemoresistant cells to taxanes.Mumenthaler SM et al
214224992011Mutant Cbl proteins as oncogenic drivers in myeloproliferative disorders.Naramura M et al
188182062008Down-regulation of micro-RNA-1 (miR-1) in lung cancer. Suppression of tumorigenic property of lung cancer cells and their sensitization to doxorubicin-induced apoptosis by miR-1.Nasser MW et al
198783562010PIM-1 kinase expression in adipocytic neoplasms: diagnostic and biological implications.Nga ME et al
120368852002Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis.Nieborowska-Skorska M et al
147645332004Pim-1 kinase inhibits STAT5-dependent transcription via its interactions with SOCS1 and SOCS3.Peltola KJ et al
118234752002Cutting edge: Transcriptional activity of NFATc1 is enhanced by the Pim-1 kinase.Rainio EM et al
187087612008Hypoxia-inducible proto-oncogene Pim-1 is a prognostic marker in pancreatic ductal adenocarcinoma.Reiser-Erkan C et al
18258101991The pim-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG.Saris CJ et al
30154201986The primary structure of the putative oncogene pim-1 shows extensive homology with protein kinases.Selten G et al
187157792008Potential roles for the PIM1 kinase in human cancer - a molecular and therapeutic appraisal.Shah N et al
157980972005Pim-1 kinase stability is regulated by heat shock proteins and the ubiquitin-proteasome pathway.Shay KP et al
106268931999Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis.Shirogane T et al
217434872012The proto-oncogene Pim-1 is a target of miR-33a.Thomas M et al
124317832002Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase.Wang Z et al
158436872005Cryptic promoter activity in the DNA sequence corresponding to the pim-1 5'-UTR.Wang Z et al
182162972008The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes.Wernig G et al
128970502003The pims and outs of survival signaling: role for the Pim-2 protein kinase in the suppression of apoptosis by cytokines.White E et al
127344362003Pim-1 phosphorylates the DNA binding domain of c-Myb.Winn LM et al
161868052006The 44 kDa Pim-1 kinase directly interacts with tyrosine kinase Etk/BMX and protects human prostate cancer cells from apoptosis induced by chemotherapeutic drugs.Xie Y et al
75400641995Transcriptional induction of pim-1 protein kinase gene expression by interferon gamma and posttranscriptional effects on costimulation with steel factor.Yip-Schneider MT et al
106375101999Identification of heterologous translocation partner genes fused to the BCL6 gene in diffuse large B-cell lymphomas: 5'-RACE and LA - PCR analyses of biopsy samples.Yoshida S et al
192766812009PIM1 protein kinase regulates PRAS40 phosphorylation and mTOR activity in FDCP1 cells.Zhang F et al
178556602007Pim-1 kinase-dependent phosphorylation of p21Cip1/WAF1 regulates its stability and cellular localization in H1299 cells.Zhang Y et al
176431172007PIM1-dependent phosphorylation of histone H3 at serine 10 is required for MYC-dependent transcriptional activation and oncogenic transformation.Zippo A et al
202158282010Pim1 regulates androgen-dependent survival signaling in prostate cancer cells.van der Poel HG et al

Other Information

Locus ID:

NCBI: 5292
MIM: 164960
HGNC: 8986
Ensembl: ENSG00000137193


dbSNP: 5292
ClinVar: 5292
TCGA: ENSG00000137193


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Jak-STAT signaling pathwayKEGGko04630
Acute myeloid leukemiaKEGGko05221
Jak-STAT signaling pathwayKEGGhsa04630
Acute myeloid leukemiaKEGGhsa05221
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
176431172007PIM1-dependent phosphorylation of histone H3 at serine 10 is required for MYC-dependent transcriptional activation and oncogenic transformation.116
185939062008Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels.109
180378962007Pim-1 regulates cardiomyocyte survival downstream of Akt.100
180569892008The 44-kDa Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells.75
155256462005Structural basis of constitutive activity and a unique nucleotide binding mode of human Pim-1 kinase.71
213828892011Signal transducers and activators of transcription-3/pim1 axis plays a critical role in the pathogenesis of human pulmonary arterial hypertension.62
164032192006Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL.61
218598462011Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma.61
162272082005Structure and substrate specificity of the Pim-1 kinase.59
182162972008The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes.55


Sai-Ching Jim Yeung

PIM1 (pim-1 oncogene)

Atlas Genet Cytogenet Oncol Haematol. 2013-04-01

Online version: http://atlasgeneticsoncology.org/gene/261/pim1-(pim-1-oncogene)

Historical Card

2000-08-01 PIM1 (pim-1 oncogene) by  Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France