Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4

Mol Cell. 2005 Aug 19;19(4):535-45. doi: 10.1016/j.molcel.2005.06.029.

Abstract

The cyclinT1/Cdk9 heterodimer that constitutes core P-TEFb is generally presumed to be the transcriptionally active form for stimulating RNA polymerase II elongation. About half of cellular P-TEFb also exists in an inactive complex with the 7SK snRNA and the HEXIM1 protein. Here, we show that the remaining half associates with the bromodomain protein Brd4. In stress-induced cells, the 7SK/HEXIM1-bound P-TEFb is quantitatively converted into the Brd4-associated form. The association with Brd4 is necessary to form the transcriptionally active P-TEFb, recruits P-TEFb to a promoter, and enables P-TEFb to contact the Mediator complex, a potential target for the Brd4-mediated recruitment. Although generally required for transcription, the P-TEFb-recruitment function of Brd4 can be substituted by that of HIV-1 Tat, which recruits P-TEFb directly for activated HIV-1 transcription. Brd4, HEXIM1, and 7SK are all implicated in regulating cell growth, which may result from their dynamic control of the general transcription factor P-TEFb.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Cyclin-Dependent Kinase 9 / genetics
  • Cyclin-Dependent Kinase 9 / metabolism
  • Gene Products, tat / genetics
  • HIV-1 / genetics
  • HeLa Cells
  • Humans
  • Molecular Sequence Data
  • Nuclear Proteins
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Positive Transcriptional Elongation Factor B / metabolism*
  • RNA Polymerase II / metabolism*
  • Transcription Factors
  • Transcription, Genetic
  • tat Gene Products, Human Immunodeficiency Virus

Substances

  • Brd4 protein, mouse
  • Gene Products, tat
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Transcription Factors
  • tat Gene Products, Human Immunodeficiency Virus
  • Positive Transcriptional Elongation Factor B
  • Cyclin-Dependent Kinase 9
  • RNA Polymerase II