Absence of R24C Mutation of the CDK4 Gene in Leukemias and Solid Tumors

Abstract

A mutation of the p16INK4a-binding domain of the cyclin dependent kinase 4 (CDK4) gene, R24C, has been reported in some cases of melanoma. This mutation prevented binding of the CDK4 inhibitor p16INK4a to CDK4. To determine the relevance of the mutation, we performed polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis in diverse types of human leukemias and solid tumors. No mobility shifts indicating sequence alterations were observed in 273 tumors and 49 cell lines from diverse kinds of tumors. These results suggest that in contrast to melanoma, in many other types of human neoplasms the mutation of the CDK4 gene is very rare. To better understand these findings, we randomly mutagenized the CDK4 gene and used the yeast two-hybrid method to screen for CDK4 mutants that had lost the ability to bind to p16INK4a. Sequence analysis and in vitro kinase assays showed that most of the mutations that disrupted interactions with p16INK4a also knocked out the activity of CDK4.This result may explain the rareness of CDK4 mutations in human tumors.

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Correspondence to Naoki Mori or Rong Yang or Norihiko Kawamata or Carl W. Miller or Hideaki Mizoguchi or H. Phillip Koeffler.

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Mori, N., Yang, R., Kawamata, N. et al. Absence of R24C Mutation of the CDK4 Gene in Leukemias and Solid Tumors. Int J Hematol 77, 259–262 (2003). https://doi.org/10.1007/BF02983783

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Key words

  • Leukemia
  • Tumor
  • CDK4 gene
  • Mutation
  • Cell cycle