Exogenous cdk4 overcomes reduced cdk4 RNA and inhibition of G1 progression in hematopoietic cells expressing a dominant-negative CBF - A model for overcoming inhibition of proliferation by CBF oncoproteins

Jianrong Lou, Wangsen Cao, Florence Bernardin, Kasirajan Ayyanathan, Frank J. Rauscher, Alan D. Friedman

Research output: Contribution to journalArticle

Abstract

Core Binding Factor (CBF) is required for the development of definitive hematopoiesis, and the CBF oncoproteins AML1-ETO, TEL-AML1, and CBFβ-SMMHC are commonly expressed in subsets of acute leukemia. CBFβ-SMMHC slows the G1 to S cell cycle transition in hematopoietic cells, but the mechanism of this effect is uncertain. We have sought to determine whether inhibition of CBF-mediated trans-activation is sufficient to slow proliferation. We demonstrate that activation of KRAB-AML1-ER, a protein containing the AML1 DNA-binding domain, the KRAB repression domain, and the Estrogen receptor ligand binding domain, also slows G1, if its DNA-binding domain is intact. Also, exogenous AML1 overcame CBFβ-SMMHC-induced inhibition of proliferation. Representational difference analysis (RDA) identified cdk4 RNA expression as an early target of KRAB-AML1 activation. Inhibition of CBF activities by KRAB-AML1-ER or CBFβ-SMMHC rapidly reduced endogenous cdk4 mRNA levels, even in cells proliferating at or near control rates as a result of exogenous cdk4 expression. Over-expression of cdk4, especially a variant which cannot bind p16(INK4a), overcame cell cycle inhibition resulting from activation of KRAB-AML1-ER, although cdk4 did not accelerate proliferation when expressed alone. These findings indicate that mutations which alter the expression of G1 regulatory proteins can overcome inhibition of proliferation by CBF oncoproteins.

Original languageEnglish (US)
Pages (from-to)2695-2703
Number of pages9
JournalOncogene
Volume19
Issue number22
DOIs
StatePublished - May 18 2000

Keywords

  • AML1-ETO
  • CBF
  • CBFβ-SMMHC
  • Cdk4
  • Leukemia

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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