Abstract
The CDKN1B gene encodes for the p27Kip1 protein, firstly characterized as a cyclin dependent kinase (CDK)-inhibitor. Germline CDKN1B pathogenic variants have been described in hereditary tumors, such as multiple endocrine neoplasia (MEN)-like syndromes and familial prostate cancer. Despite its central role in tumor progression, for a long time it has been proposed that CDKN1B was very rarely somatically mutated in human cancer and that its expression levels were almost exclusively regulated at post-transcriptional level. Yet, the advent of massive parallel sequencing has partially subverted this general understanding demonstrating that, at least in some types of cancer, CDKN1B is mutated in a significant percentage of analyzed samples. Recent works have demonstrated that CDKN1B can be genetically inactivated and this occurs particularly in sporadic luminal breast cancer, prostate cancer and small intestine neuroendocrine tumors. However, a clear picture of the extent and significance of CDKN1B mutations in human malignances is still lacking. To fill this gap, we interrogated the COSMIC, ICGC, cBioPortal, and TRANSFAC data portals and current literature in PubMed, and reviewed the mutational spectrum of CDKN1B in human cancers, interpreting the possible impact of these mutations on p27Kip1 protein function and tumor onset and progression.
Highlights
IntroductionThe CDKN1B gene encodes for the p27Kip protein (hereafter p27), firstly characterized as an inhibitor of cell cycle progression for its ability to bind and regulate a broad range of cyclinCDK (cyclin-dependent kinase) complexes [1]
The CDKN1B gene encodes for the p27Kip1 protein, firstly characterized as an inhibitor of cell cycle progression for its ability to bind and regulate a broad range of cyclinCDK complexes [1]
Our review of the literature and available datasets reporting the mutations of CDKN1B gene in human cancers indicates that these events are generally rare in sporadic cancer, with the exception of luminal breast cancer (LBC), prostate cancer (PC), and small intestine neuroendocrine tumors (SI-NET)
Summary
The CDKN1B gene encodes for the p27Kip protein (hereafter p27), firstly characterized as an inhibitor of cell cycle progression for its ability to bind and regulate a broad range of cyclinCDK (cyclin-dependent kinase) complexes [1]. CDKN1B belongs to a family of CDK inhibitor (CKI) genes that comprises CDKN1A (encoding for p21Waf1) and CDKN1C (encoding for p57Kip). The three CKI proteins share a region of high homology at their N-terminal portion, encompassing the cyclin- and the CDK-binding domains [2, 3]. This region confers the ability to bind and inhibit, with different stoichiometry, all cyclin/CDKs complexes, eventually controlling progression through the cell cycle. Many studies have clearly demonstrated that p27 has the ability to interact with many different proteins and represents a target for many signal transduction pathways, thereby accomplishing a number of previously unexpected and so-called non-canonical functions [5] (Figure 1)
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