Role of the p16 tumor suppressor gene in cancer.

Abstract

Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. p16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor gene. Its mechanism of action as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, and thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and results in cell-cycle arrest. Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear. Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers.

utImmunohistochemical Detection of the Alternate INK4a-Encoded Tumor Suppressor Protein p14ARF in Archival Human Cancers and Cell Lines Using Commercial Antibodies: Correlation with p16INK4a Expression

“…p16 INK4a acts as a retinoblastoma protein (pRB) agonist by inhibiting the phosphorylation of pRB by activated cyclin-dependent kinases 4 and 6 (2). The principal methods of p16 INK4a inactivation are homozygous deletion of the gene, promoter methylation of exon 1␣, and intragenic mutation (3). The frequency of p16 INK4a inactivation in human neoplasia rivals that of p53.…”

Adenoviral vector containing wild-type p16 suppresses prostate cancer growth and prolongs survival by inducing cell senescence

“…41 Thus, p16 inactivation by genetic mutations, allelic loss, or hypermethylation of the promoter is a common event not only in prostate cancer but also in other cancers. [22][23][24][25]42 In this study, we found that human prostate cancer was suppressed markedly with a replication-defective, recombinant, E1/E3-deleted adenovirus containing a truncated Rous sarcoma virus (RSV) promoter and the wild-type (wt) p16 tumor-suppressor gene. Animals bearing human prostate cancer xenografts treated with AdRSVp16 also had longer survival.…”

A diagnostic algorithm for atypical spitzoid tumors: guidelines for immunohistochemical and molecular assessment

“…12,15 The p16 protein, encoded by the gene CDKN2A on chromosome 9p, is critical to tumor suppression and has an important role in melanomas. 16,17 p16 Ink4a is a cyclin-dependent kinase inhibitor that blocks formation of the catalytically active CDK4/6-cyclin D complex, thereby preventing the phosphorylation of the retinoblastoma (Rb) gene and passage through the cell cycle's G1/S checkpoint (Figure 2a). [17][18][19][20] As a tumor suppressor, p16 is found in low levels in normal proliferating cells but events such as DNA damage, oncogenic stress, and aging trigger its Figure 1 Four scenarios from the proposed diagnostic algorithm for the assessment of the malignant potential of atypical spitzoid tumors.…”