A p16 ^INK4a -Insensitive CDK4 Mutant Targeted by Cytolytic T Lymphocytes in a Human Melanoma

Abstract

A mutated cyclin-dependent kinase 4 (CDK4) was identified as a tumor-specific antigen recognized by HLA-A2. 1-restricted autologous cytolytic T lymphocytes (CTLs) in a human melanoma. The mutated CDK4 allele was present in autologous cultured melanoma cells and metastasis tissue, but not in the patient's lymphocytes. The mutation, an arginine-to-cysteine exchange at residue 24, was part of the CDK4 peptide recognized by CTLs and prevented binding of the CDK4 inhibitor p16INK4a, but not of p21 or of p27KIP1. The same mutation was found in one additional melanoma among 28 melanomas analyzed. These results suggest that mutation of CDK4 can create a tumor-specific antigen and can disrupt the cell-cycle regulation exerted by the tumor suppressor p16INK4a.

Ovarian cancer cells that coexpress endogenous Rb and p16 are insensitive to overexpression of functional p16 protein

“…This suggested the inability of the ectopic p16 to completely inhibit cyclin D1/CDK4/6 complex kinase activity and raised the possibility that these cells might contain an alternative form of CDK4 and/or CDK6 that was insensitive to inhibition by p16. A mutation that results in an arg to cys transition in CDK4 and renders it unable to be bound and inhibited by p16 has been reported in familial melanomas (Wolfel et al, 1995;Zuo et al, 1996). However, we found that neither ES-2 nor NIH OVCAR-3 cells harbored this mutation (data not shown).…”

A genetic screen to identify genes that rescue the slow growth phenotype of c-myc null fibroblasts

“…Recently, the cyclin-dependent kinase CDK4 was identi®ed as a critical target of c-Myc since it could partially alleviate the c-myc null growth defect (Hermeking et al, 2000). However, in our hands a cmyc null derivative that over-expressed the tumorderived CDK4/R24C mutant (Wolfel et al, 1995) did not even show a partial rescue of the growth defect (data not shown). This apparent discrepancy may be caused by the fact that the CDK4/R24C mutant has a reduced ability to bind the CDK4/6 inhibitor p16 INK4A and therefore more experiments are required to clarify this issue.…”

Re-expression of p16INK4a in mesothelioma cells results in cell cycle arrest, cell death, tumor suppression and tumor regression

“…Rearrangements or over-expression of cyclin D family members have been reported in a wide variety of cancers, but not in mesothelioma (Sherr, 1996). In a similar manner, mutations in the p16 INK4a associated cyclin-dependent-kinase (cdk4) have been reported in certain kindreds of familial melanoma (Wolfel et al, 1995;Zuo et al, 1996). These reported cdk4 mutations render the kinase insensitive to p16 INK4a -mediated inhibition and thus allow continued G-phase cyclin mediated phosphorylation of pRB and lack of cell cycle arrest.…”