A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma

  title={A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma},
  author={Thomas Wolfel and M. Hauer and Jörg Schneider and Manuel Serrano and C Wolfel and E Klehmann-Hieb and Etienne de Plaen and Thomas Hankeln and K H Meyer zum B{\^u}schenfelde and David H. Beach},
  pages={1281 - 1284}
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… 

p16(MTS-1/CDKN2/INK4a) in cancer progression.

P16 is a major tumor-suppressor gene whose frequent loss occurs early in many human cancers and is believed that loss of p16 is an early and often critical event in tumor progression.

Haploinsufficiency of p18INK4c Sensitizes Mice to Carcinogen-Induced Tumorigenesis

It is shown that treatment of p18 null and heterozygous mice with a chemical carcinogen resulted in tumor development at an accelerated rate and p18 is a haploinsufficient tumor suppressor in mice.

CDKN 2 A / p 16 Is Inactivated in Most Melanoma Cell Lines '

Data indicate that 55 of 60 melanoma cell lines demonstrated some aberration of CDKN2A or CDK4, thus sug gesting that this pathway is a primary genetic target in melanoma devel opment.

Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma

An Arg24Cys mutation in CDK4 is described, which generates a dominant oncogene that is resistant to normal physiological inhibition by p16INK4a in two unrelated melanoma families which do not carry germline p16inks4a mutations.

A CDKN 2 A Mutation in Familial Melanoma that Abrogates Binding of p 16 INK 4 a to CDK 4 but not CDK 6

The characterization of a novel strain of human diploid fibroblasts from an individual who is homozygous for the R24P mutation in p16 is described, suggesting that CDK4 and CDK6 are not functionally redundant and underscore the importance ofCDK4 in the development of melanoma.

Identification of a new peptide recognized by autologous cytolytic T lymphocytes on a human melanoma.

Interestingly, some of the melanoma sublines of LG2-MEL have lost the wild-type allele of gene OS-9, and those sublines appear to grow faster in vitro than the sublines that retained theWild- type allele, suggesting that this loss of heterozygosity may favor tumor progression.

Isolation of a New Melanoma Antigen, MART-2, Containing a Mutated Epitope Recognized by Autologous Tumor-Infiltrating T Lymphocytes1

Using cDNA expression cloning, a cDNA encoding a novel human melanoma Ag, MART-2 (melanoma Ag recognized by T cells-2), recognized by HLA-A1-restricted CD8+ T cells from tumor-infiltrating

Melanoma genetics: an update with focus on the CDKN2A(p16)/ARF tumor suppressors.

  • M. Piepkorn
  • Biology
    Journal of the American Academy of Dermatology
  • 2000
In this learning activity, participants should be familiar with the historical aspects of melanoma genetics and have a greater understanding of the CDKN2A(p16)/ARF tumor suppressor genes.

A CASP-8 Mutation Recognized by Cytolytic T Lymphocytes on a Human Head and Neck Carcinoma

The identification of an antigen recognized by autologous cytolytic T lymphocytes on a human squamous cell carcinoma of the oral cavity is reported, encoded by a mutated form of the CASP-8 gene, suggesting that a significant fraction of the point mutations generating a tumor antigen also play a role in the tumoral transformation or progression.



Mutations and altered expression of p16INK4 in human cancer.

Results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation.

Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition

It is reported here that pi6 can act as a potent and specific inhibitor of progression through the Gl phase of the cell cycle, and it is demonstrated that several tumour-derived alleles of p16 encode functionally compromised proteins.

Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas.

Observations provide the first evidence for amplification of a gene encoding a cell division cycle protein kinase, complement recent data indicating that genes encoding D-type cyclins are targets of chromosomal rearrangement and gene amplification in tumor cells, and suggest that CDK4 amplification might contribute to oncogenesis.

The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas

The cloning of a cDNA is reported that directs the expression of the antigen recognized by HLA-A2 melanoma patients, and this cDNA corresponds to the transcript of the tyrosinase gene.

CDK4 amplification is an alternative mechanism to p16 gene homozygous deletion in glioma cell lines.

Examination of glioma cell lines for amplification-associated overexpression of the CDK4 gene as an alternative mechanism for abrogating the growth-regulatory effects of p16 indicates that increased cdk4 kinase activity is important to glial tumor development.

Somatic mutations of the MTS (multiple tumor suppressor) 1/CDK4l (cyclin-dependent kinase-4 inhibitor) gene in human primary non-small cell lung carcinomas.

The results suggest that inactivation of MTS1/CDK4l plays an important role during carcinogenesis of NSCLC.

Mutations associated with familial melanoma impair p16INK4 function

Cell division is controlled by a series of positive and negative regulators which act at sequential points throughout the cell cycle. Disturbance of these checks could contribute to cancer by

A cell cycle regulator potentially involved in genesis of many tumor types.

Findings suggest that MTS1 mutations are involved in tumor formation in a wide range of tissues.

A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas

The identification of another gene that also directs the expression of an antigen recognized on most melanomas by CTL clones that are restricted by HLA-A2 is reported, which is unrelated to any known gene.