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

  title={Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma},
  author={Lin Zuo and John R Weger and Qin Yang and Alisa M. Goldstein and Margaret A. Tucker and Graeme J. Walker and Nicholas K. Hayward and Nicholas C. Dracopoli},
  journal={Nature Genetics},
Protein complexes consisting of a cyclin-dependent kinase (CDK4 or CDK6) and cyclin D control passage through the G1 checkpoint of the cell cycle by phosphorylating the retinoblastoma (RB) protein1. The ability of these complexes to phosphorylate RB is inhibited by a family of low molecular weight proteins including p16INK4a (refs 2,3), p15iNK4B (ref 4)? and p18 (ref 5) Germline mutations in the p16INK4a gene have been identified in approximately half of families with hereditary melanoma6–12… 

Germline mutations of the CDKN2 gene in UK melanoma families.

Two novel CDKN2 mutations are identified (88delG and Ala118Thr) which are likely to be associated with the development of melanoma, because of their co-segregation with the disease and their likely functional effect on the CD KN2 protein.

CDKN2a/p16INK4a mutations and lack of p19ARF involvement in familial melanoma kindreds.

The hypothesis that the CDKN2a is a melanoma susceptibility gene in familial melanoma, whereas the p19ARF gene does not seem to play a significant role is supported.

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.

Screening of germline mutations in the CDK4, CDKN2C and TP53 genes in familial melanoma: A clinic‐based population study

The present investigation reports the results of screening the 100 Swedish melanoma families for germline mutations in the CDK4, CDKN2C and TP53 genes, finding no disease‐related mutations were detected in the coding regions.

Absence of Mutations in the CDKN2 Binding Site of CDK4 in Childhood Acute Lymphoblastic Leukemia

The absence of point mutations in the CDKN2-binding site of CDK4 is reported in 100 cases of childhood ALL, 2 cases of Childhood chronic myeloid leukemia and 9 hematologic cell lines screened by PCR-SSCP, thereby minimizing the possibility of the existence of these specificCDK4 mutations in childhood ALL.

p16/CDKN2 and CDK4 gene mutations in sporadic melanoma development and progression

The absence of the CDKN2 mutation detected in the corresponding primary tumors suggests that 9p21 homozygous deletion may play a major role in the metastatic spreading of this type of tumor, and none of the cases analyzed showed the presence of an Arg24Cys mutation, which functionally protects CDK4 from p16 inhibition.

CDKN2A and CDK4 mutation analysis in Italian melanoma-prone families: functional characterization of a novel CDKN2A germ line mutation

The results, obtained in a heterogeneous group of families, support the view that inactivating mutations of CDKN2A contribute to melanoma susceptibility more than activating mutations ofCDK4 and that other genetic factors must be responsible for melanoma clustering in a high proportion of families.

Several noncontiguous domains of CDK4 are involved in binding to the P16 tumor suppressor protein.

Results indicate that several noncontiguous amino acid sequences on CDK4 are required for binding to p16, which suggests the existence of multiple sites of interaction with p16.

A CDKN2A mutation in familial melanoma that abrogates binding of p16INK4a to CDK4 but not CDK6.

The characterization of a novel strain of human diploid fibroblasts from an individual who is homozygous for the R24P mutation in p16INK4a suggests that CDK4 and CDK6 are not functionally redundant and underscore the importance ofCDK4 in the development of melanoma.

Two p16 (CDKN2A) germline mutations in 30 Israeli melanoma families

Functional analysis indicated that the novel G122V variant retained some capacity to interact with cyclin dependent kinases (CDKs) in vitro, yet it was significantly impaired in its ability to cause a G1 cell cycle arrest in human diploid fibroblasts.



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

Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma.

A family with inherited melanoma is described in which a novel mutation in exon 2 of the p16INK4A gene segregates with the disease, and it is concluded that family members carrying this germline mutation in the p 16INK4a gene are predisposed to melanoma.

Rarity of somatic and germline mutations of the cyclin-dependent kinase 4 inhibitor gene, CDK4I, in melanoma.

Evidence from cytogenetics, multipoint linkage analyses of familial melanoma, and loss of heterozygosity studies of familial and sporadic melanomas support localization of a melanoma susceptibility

Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds

This work has analysed CDKN2 coding sequences in 15 Dutch familial atypical multiple mole-melanoma (FAMMM) syndrome pedigrees, and identified a 19 basepair (bp) germline deletion in 13 of them, which greatly strengthen the notion that p16 is indeed MLM.

Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds.

In seven Australian melanoma kindreds, CDKN2 mutations were found to segregate with the putative melanoma chromosome previously assigned by 9p haplotype analysis, providing additional strong support that theCDKN2 gene is the chromosome 9p21 familial melanoma locus.

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

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.

Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function.

An 18-kD human protein, p18, is identified that is a homolog of the cyclin D-CDK4 inhibitors p16 (INK4A/MTS1) and p14 (MTS2/INK4B) and exhibits no detectable interaction with the other known CDKs.

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.

Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus

A locus for familial melanoma, MLM, has been mapped within the same interval on chromosome 9p21 as the gene for a putative cell cycle regulator, p16INK4 (CDKN2) MTS1, suggesting that CDKN2 is a good candidate for MLM.