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Exogenous cdk4 overcomes reducedcdk4 RNA and inhibition of G1 progression in hematopoietic cells expressing a dominant-negative CBF – a model for overcoming inhibition of proliferation by CBF oncoproteins

Oncogene volume 19, pages 2695–2703 (2000)Cite this article

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 p16INK4a, 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.

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Acknowledgements

We thank W Wang and M Britos-Bray for technical assistance, S Hiebert for the AML1B cDNA, C Sherr for the murine cdk4 and cyclin D2 cDNAs, and N Speck for CBFβ antisera. AD Friedman is supported by The Children's Cancer Foundation and NIH grant HL51388 and is a Leukemia & Lymphoma Society Scholar. FJ Rauscher is a scholar of the Pew Program in Biomedical Sciences. F Bernardin is supported by the Foundation of France Leukemia Committee and by the Leukemia Research Foundation.

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Authors and Affiliations

  1. Division of Pediatric Oncology, The Johns Hopkins Oncology Center, Baltimore, 21231, Maryland, MD, USA

    Jianrong Lou, Wangsen Cao, Florence Bernardin & Alan D Friedman

  2. The Wistar Institute, Philadelphia, 19104, Pennsylvania, PA, USA

    Kasirajan Ayyanathan & Frank J Rauscher III

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  1. Jianrong Lou
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  2. Wangsen Cao
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Lou, J., Cao, W., Bernardin, F. et al. Exogenous cdk4 overcomes reducedcdk4 RNA and inhibition of G1 progression in hematopoietic cells expressing a dominant-negative CBF – a model for overcoming inhibition of proliferation by CBF oncoproteins. Oncogene 19, 2695–2703 (2000). https://doi.org/10.1038/sj.onc.1203588

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