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Review
. 2010 Sep;6(9):1461-78.
doi: 10.2217/fon.10.106.

Why target PIM1 for cancer diagnosis and treatment?

Nancy S Magnuson  1 , Zeping Wang, Gang Ding, Raymond Reeves
Affiliations
Review

Why target PIM1 for cancer diagnosis and treatment?

Nancy S Magnuson et al. Future Oncol. 2010 Sep.

Abstract

The highly conserved proto-oncogenic protein PIM1 is an unusual serine or threonine kinase, in part because it is constitutively active. Overexpression of PIM1 experimentally leads to tumor formation in mice, while complete knockout of the protein has no observable phenotype. It appears to contribute to cancer development in three major ways when it is overexpressed; by inhibiting apoptosis, by promoting cell proliferation and by promoting genomic instability. Expression in normal tissues is nearly undetectable. However, in hematopoietic malignancies and in a variety of solid tumors, increased PIM1 expression has been shown to correlate with the stage of disease. This characteristic suggests it can serve as a useful biomarker for cancer diagnosis and prognosis. Several specific and potent inhibitors of PIM1’s kinase activity have also been shown to induce apoptotic death of cancer cells, to sensitize cancer cells to chemotherapy and to synergize with other anti-tumor agents, thus making it an attractive therapeutic target.

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Figures

Figure 1
Figure 1. PIM1 is involved in a variety of mechanisms that result in the inhibition of apoptosis
Increased PIM1 expression in cells promotes cell survival and the increases of PIM1 can result from a variety of factors. These include cytokine and hormone stimulation, exposure to hypoxia and stress (e.g., heat shock and reactive oxygen species) and constitutively activated tyrosine kinases that result from translocations (e.g., BCR-Abl and FLT3-ITD) that cause continuous activation of STAT5. The high levels of PIM1 facilitate the phosphorylation of BAD on Ser112, which promotes its binding to 14-3-3 and sequesters it away from the mitochondria. PIM1 can also phosphorylate and inactivate the proapoptotic proteins ASK1 and FOX3a, and phosphorylate and stabilize MDM2, which maintains its E3 ligase activity on targets such as FOX3a. BAD: Bcl-2-associated death promoter; BCR: Breakpoint cluster region; FLT: Fms-like tyrosine kinase; ITD: Internal tandem duplication; MDM: Double-minute chromosome; STAT: Signal transducers and activators of transcription.
Figure 2
Figure 2. PIM1 is involved in regulating the activity of a number of proteins associated with cell cycle progression
The proteins that PIM1 is known to phosphorylate are indicated in the diagram at the various stages of the cell cycle. Starting at the G1 phase of the cell cycle, CDC25A is a dual specificity phosphatase that is required for progression from G1 to the S phase of the cell cycle. PIM1 phosphorylates CDC25A, which promotes this activity. p21Cip1/WAF1 is a cell cycle inhibitor and inhibits the activity of cyclin E/CDK2 and cyclin D/CDK4 complexes, and thus functions as a regulator of cell cycle progression at G1 and G2/M phases. In some cells, PIM1 phosphorylation of p21Cip1/WAF1 results in the inactivation of p21Cip1/WAF1 by promoting its translocation to the cytoplasm. p27Kip1, also a cell cycle inhibitor, binds to cyclin D either alone, or when complexed to its catalytic subunit CDK4. PIM1 phosphorylation of p27Kip1 inactivates its activity. CDC25C is a phosphatase that directs dephosphorylation of cyclin B-bound CDC2 and triggers entry into mitosis. CDC25C-associated kinase 1 (C-TAK1) contributes to the regulation of CDC25C phosphatase and the MAPK scaffold protein KSR1 in vivo through the generation of 14-3-3-binding sites. PIM1 phosphorylation of C-TAK1 reduces its kinase activity thereby reducing its ability to phosphorylate and inactivate CDC25C. NuMA is essential for mitotic spindle formation and changes its cellular localization with the progression of the cell cycle. NuMA is required for stabilizing and tethering the spindles to the poles and aligning them in a dynein–dynactin-dependent manner. PIM1 phosphorylates NuMA and associates with it and HP1β, dynein and dynactin in a complex. However, when a kinase-dead form of PIM1 is introduced into cells, fragmentation of chromosomes is observed. HP1β is a member of a family of small proteins thought to contribute to the transcriptional silencing of heterochromatin. PIM1 phosphorylation of HP1γ, an isoform of HP1β, was demonstrated to contribute to heterochromatin silencing. NuMA: Nuclear mitotic apparatus protein.
Figure 3
Figure 3. Potential contribution of PIM1 towards introducing mutations mediated by proliferating cell nuclear antigen in translesion DNA synthesis
High levels of PIM1 have been shown to mediate the phosphorylation and inactivation of p21Cip1/WAF1, thereby promoting the progression through G1 and G2/M phases of the cell cycle. This occurs in part by inhibiting the binding of PCNA to p21Cip1/WAF1. PCNA is the processivity factor for DNA polymerase δ and ε. It is best known for its involvement in DNA synthesis and DNA repair. The dissociation of PCNA from p21Cip1/WAF1 following phosphorylation of p21Cip1/WAF1 by PIM1 in the nucleus restores the function of the DNA synthesis machinery. However, it also reduces the accuracy of translesion DNA synthesis potentially leading to the introduction of mutations. This may be a contributing factor to chromosome instability that is observed in cell lines overexpressing PIM1. PCNA: Proliferating cell nuclear antigen.
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