Cyclin D1 suppresses retinoblastoma protein-mediated inhibition of TAF(II)250 kinase activity

Jennifer L. Siegert, John J. Rushton, William R. Sellers, William G. Kaelin, Paul D. Robbins

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18 Scopus citations

Abstract

The retinoblastoma tumor suppressor protein has been shown to bind directly and inhibit a transcriptionally-important amino-terminal kinase domain of TATA-binding protein-associated factor TAF(II)250. Cyclin D1 also is able to associate with the amino terminus of TAF(II)250 in a region very similar to or overlapping the Rb-binding site. In this study, we have examined whether cyclin D1 affects the functional interaction between Rb and TAF(II)250. We observed that when cyclin D1 is coincubated with Rb and TAF(II)250, the ability of Rb to inhibit TAF(II)250 kinase activity is effectively blocked. However, cyclin D1 by itself has no apparent effect on TAF(II)250 kinase activity. We further found that the Rb-related protein p107 can inhibit TAF(II)250 kinase activity, and this inhibition is likewise alleviated by cyclin D1. Cyclin D1 prevents the kinase-inhibitory effect of an Rb mutant unable to bind to D-type cyclins, indicating that it is acting through its association with TAF(II)250 and not with Rb. However, we found no evidence of TAF(II)250-binding competition between Rb and cyclin D1 in vitro. The adenovirus E1A protein, which also binds to both Rb and TAF(II)250, exhibited a suppressive effect on Rb-mediated kinase inhibition similar to that seen with cyclin D1. Our results suggest a novel means by which cyclin D1 may be able to independently regulate the activity of Rb.

Original languageEnglish (US)
Pages (from-to)5703-5711
Number of pages9
JournalOncogene
Volume19
Issue number50
DOIs
StatePublished - Nov 23 2000

Bibliographical note

Funding Information:
This work was supported by a public health service grant (55227) from the National Cancer Institute to PD Robbins and by a predoctoral research training grant from the United States Army to JL Siegert. We thank Z Shao and J Adnane for reagents and critical work leading up to this study. We would also like to thank M Ewen and C McMahon for kindly providing the cyclin D1 baculovirus, R Tjian and S Ruppert for providing TAFII250 expression constructs, Z Burton and L Lei for the RAP74 construct, and D Rowe for supplying the E1A construct.

Keywords

  • Cyclin D1
  • Kinase
  • Rb
  • TAF(II)250

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