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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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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DOI: https://doi.org/10.1038/sj.onc.1203588
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