Expression and alternative splicing of the cyclin-dependent kinase inhibitor-3 gene in human cancer

Abstract

The cyclin-dependent kinase inhibitor-3 (CDKN3) gene encodes a dual-specificity protein tyrosine phosphatase that dephosphorylates CDK1/CDK2 and other proteins. CDKN3 is often overexpressed in human cancer, and this overexpression correlates with reduced survival in several types of cancer. CDKN3 transcript variants and mutations have also been reported. The mechanism of CDKN3 overexpression and the role of CDKN3 transcript variants in human cancer are not entirely clear. Here, we review the literature and provide additional data to assess the correlation of CDKN3 expression with patient survival. Besides the full-length CDKN3 encoding transcript and a major transcript that skips exon 2 express in normal and cancer cells, minor aberrant transcript variants have been reported. Aberrant CDKN3 transcripts were postulated to encode dominant-negative inhibitors of CDKN3 as an explanation for overexpression of the perceived tumor suppressor gene in human cancer. However, while CDKN3 is often overexpressed in human cancer, aberrant CDKN3 transcripts occur infrequently and at lower levels. CDKN3 mutations and copy number alternation are rare in human cancer, implying that neither loss of CDKN3 activity nor constitutive gain of CDKN3 expression offer an advantage to tumorigenesis. Recently, it was found that CDKN3 transcript and protein levels fluctuate during the cell cycle, peaking in mitosis. Given that rapidly growing tumors have more mitotic cells, the high level of mitotic CDKN3 expression is the most plausible mechanism of frequent CDKN3 overexpression in human cancer. This finding clarifies the mechanism of CDKN3 overexpression in human cancer and questions the view of CDKN3 as a tumor suppressor.

CDKN3 promotes cell proliferation, invasion and migration by activating the AKT signaling pathway in esophageal squamous cell carcinoma

“…Cyclin-dependent kinase inhibitor 3 (CDKN3) serves crucial roles in the cell cycle and proliferation (8)(9)(10). CDKN3 performs its functions by binding to cyclin proteins, which results in dephosphorylation of CDK1 and CDK2 proteins and inhibition of cell cycle progression (11)(12)(13).…”

Long non‑coding RNA MLK7‑AS1 promotes proliferation in human colorectal cancer via downregulation of p21 expression

“…Recently, it has been revealed that lncRNAs can increase or inhibit the expression levels of target genes to exert effects in cancer progression (24). CKIs are known to be critical tumor suppressors in various cancers and play key roles in cell cycle regulation (10,22,28) Importantly, CKIs are involved in the biological role of lncRNAs (28,39,40). The abnormal methylation in promoter regions of CKIs leads to gene expression inhibition, thus contributing to alteration of cell cycle (41,42).…”

“…Cyclin-dependent kinase inhibitors (CKIs) are known to modulate cell cycle progression and function as tumor suppressors (21,22). p21 is an essential member of CKIs family, which includes p15, p16, p27 and p57 (21).…”

Integrated analysis of a compendium of RNA-Seq datasets for splicing factors

“…To identify the DAS events, we performed DAS analysis 57,58,59,60,61 . Briefly, the raw RNA-Seq reads first were aligned to mouse genome (mm9) using STAR 62 with default settings, and those uniquely mapped reads were retained to calculate the counts of the reads for each exon and each exon-exon junction annotated in the UCSC knownGene (mm9) table 63 using the Python package HTSeq 64 .…”