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J. Biol. Chem., Vol. 276, Issue 11, 8524-8534, March 16, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/11/8524    most recent M008371200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chu, C. Articles by Kohtz, D. S. Search for Related Content PubMed PubMed Citation Articles by Chu, C. Articles by Kohtz, D. S. Social Bookmarking                      What's this?

Identification of the E2A Gene Products as Regulatory Targets of the G₁ Cyclin-dependent Kinases^*

Caryn Chu and D. Stave Kohtz

From the Department of Pathology, Mount Sinai School of Medicine, New York, New York 10029

The E2A gene products, E12 and E47, are multifunctional transcription factors that as homodimers regulate B cell development, growth, and survival. In this report, the E2A gene products are shown to be targets for regulation by the G₁ cyclin-dependent kinases. Two novel G₁ cyclin-dependent kinase sites are identified on the N-terminal domain of E12/E47. One site displays homology to a preferential D-type cyclin-dependent kinase site (serine 780) on the retinoblastoma susceptibility gene product (pRB) and, consistent with this homology, is more efficiently phosphorylated by cyclin D1-CDK4 than by the other cyclin-dependent kinases (CDK) that were tested. The second kinase site is phosphorylated by both cyclin D1-CDK4 and cyclin A/E-CDK2 complexes. Mutation studies indicated that phosphorylation of the cyclin D1-CDK4 site, or more potently, of both the cyclin D1-CDK4 and cyclin A/E-CDK2 sites, negatively regulates the growth suppressor function associated with the N-terminal domain of E12/E47. Transient expression studies showed that ectopic expression of cyclin D1 or E negatively regulates sequence-specific activation of gene transcription by E12/E47. Analysis of site mutants, however, indicated that inhibition of E12/E47 transcriptional activity did not require the N-terminal G₁ cyclin-dependent kinase sites. Together, the results suggest that the growth suppressor and transcriptional activator functions of E12/E47 are targets for regulation by G₁ cyclin-dependent kinases but that the mechanisms of regulation for each function are distinct.

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