Key Points
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Pim kinases are frequently overexpressed in human haematological malignancies and solid cancers, and they are often associated with strongly elevated MYC levels.
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Overexpression of Pim kinases is associated with a good prognosis in some solid cancers, such as prostate cancer, but is associated with a poor prognosis in other solid cancers and most haematological malignancies.
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Pim kinases are serine/threonine kinases that have consititutive activity (and therefore lack the need for post-translational activation). As their mRNA and proteins have a very short half-life, the activity of Pim kinases is largely regulated at the transcriptional and translational levels.
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Pim kinases mediate survival signalling through phosphorylation of BCL-2-associated agonist of cell death (BAD), which induces release of the anti-apoptotic BCL-2 and BCL-2-like 1 (also known as BCL-X) proteins and thus lowers the threshold for apoptosis. Pim kinases might also induce BAD activities towards the regulation of glucose metabolism.
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PIM2 can regulate cap-dependent translation in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner, and in parallel to the PI3K–Akt pathway. This activity has been found to be relevant for certain human haematological malignancies, and is not shared with PIM1 or PIM3.
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PIM1 can bind to MYC–MAX complexes and phosphorylate H3S10 at E-boxes, thereby setting off a cascade of events that leads to transcriptional pause release of RNA polymerase II at MYC-driven promoters. It remains unknown whether this activity contributes to tumorigenesis in vivo or whether other Pim family members share this activity with PIM1.
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Pim kinases are promising targets for pharmacological inhibition, as the structural conformation of the ATP-binding pocket in the active site is different from that of other protein kinases, which in theory should allow the design of specific and selective inhibitors. The lack of any overt phenotypes in Pim1−/−;Pim2−/−;Pim3−/− mice indicates that such drugs might have a low toxicity profile.
Abstract
Pim oncogenes are overexpressed in a wide range of tumours from a haematological and epithelial origin. Pim genes encode serine/threonine kinases that have been shown to counteract the increased sensitivity to apoptosis induction that is associated with MYC-driven tumorigenesis. Recently, considerable progress has been made in characterizing the pathways of PIM-mediated survival signalling. Given the unique structure of their active site and the minimal phenotype of mice mutant for all Pim family members, these oncogenes might be promising targets for highly specific and selective drugs with favourable toxicity profiles. In this Review, we discuss the physiological functions and oncogenic activities of Pim kinases.
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The authors would like to thank R. van Amerongen for critical reading of the manuscript. The authors regret not being able to cite all relevant references owing to space limitations.
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Glossary
- Long terminal repeat
-
LTR. Identical sequences at both ends of the proviral genome comprised of enhancer elements (U3 region), a promoter (U3/R boundary) and a polyadenylation signal (R/U5 boundary). Facilitates proviral integration and regulates expression of viral mRNA and so the replication the virus.
- Pre-B cell lymphomas
-
Hyperplastic growth and transformation of large pre-B cells owing to the accumulation of mutations that affect their ability to keep pre-B cell receptor and MYC levels at bay.
- Kozak sequence
-
The consensus gccRccAUGG (R represents a purine) sequence in the 5′ region of eukaryotic mRNA that is the optimal ribosomal-binding site and facilitates initiation of translation.
- Primary response gene
-
PRG. Upon mitogenic stimuli, upregulation of PRG transcription is rapid but transient and does not require de novo protein synthesis. Most PRGs are transcription factors and propagate signalling by regulating expression of a cascade of downstream secondary target genes.
- Cap-dependent translation
-
Recognition of precursor mRNA transcripts containing a 7-methylguanosine cap (m7G) at their 5′ end and assembly of 40S ribosomal subunit with the help of eukaryotic initiation factors, after which 40S subunit scans towards the 3′ end of mRNA till the first start codon (AUG).
- 5′-m7G cap
-
A post-transcriptional modification of the first 5′ nucleotide of eukaryotic mRNA forming a m7G(5′)ppp(5′)N cap. Protects mRNA from degradation, binds EIF4E, and recruits eIF4F and 40S ribosome subunit to initiate translation.
- Stem-loop-pair
-
Structurally conserved element formed by a set of A and U nucleotides (UX2UX2A) in the eIF4E-sensitive element (4E-SE) of the 3′ UTR. Binds to EIF4E and promotes nuclear export of the mRNA.
- β-selection
-
A positive selection event during the maturation of precursor T cells upon successful rearrangement of the T cell receptor (TCR) β-chain locus that allows pairing to the pre-Tα chain to form a functional pre-TCR. This allows transition from double-negative to the double-positive stage of T cell development.
- Common γ-chain
-
A cytokine receptor subunit, CD132, common to receptor complexes of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. It is required for functional signalling downstream of these cytokines. Mutations in the common γ-chain impair lymphocyte development.
- Somatic hypermutation
-
SHM. The controlled process of mutation in the variable region of immunoglobulin locus that diversifies the range of B cell receptors used by the immune system to fine-tune the recognition of pathogens.
- E-box
-
A DNA element with a consensus sequence CANNTG that is recognized and bound by MYC and MAX transcription factors that contain the basic helix–loop–helix structural motif.
- Transcriptional pause
-
An RNA Pol II molecule that has not engaged in a productive transcription elongation and has paused at the promoter-proximal region under the control of negative regulators such as NELF and DSIF.
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Nawijn, M., Alendar, A. & Berns, A. For better or for worse: the role of Pim oncogenes in tumorigenesis. Nat Rev Cancer 11, 23–34 (2011). https://doi.org/10.1038/nrc2986
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DOI: https://doi.org/10.1038/nrc2986
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