BRCA1 effects on the cell cycle and the DNA damage response are linked to altered gene expression

J Biol Chem. 2000 Jan 28;275(4):2777-85. doi: 10.1074/jbc.275.4.2777.

Abstract

The breast and ovarian cancer susceptibility gene product BRCA1 has been reported to be expressed in a cell cycle-dependent manner; possess transcriptional activity; associate with several proteins, including the p53 tumor suppressor; and play an integral role in certain types of DNA repair. We show here that ectopic expression of BRCA1 using an adenovirus vector (Ad-BRCA1) leads to dephosphorylation of the retinoblastoma protein accompanied by a decrease in cyclin-dependent kinase activity. Flow cytometric analysis on Ad-BRCA1-infected cells revealed a G(1) or G(2) phase accumulation. High density cDNA array screening of colon, lung, and breast cancer cells identified several genes affected by BRCA1 expression in a p53-independent manner, including DNA damage response genes and genes involved in cell cycle control. Notable changes included induction of the GADD45 and GADD153 genes and a reduction in cyclin B1 expression. Therefore, BRCA1 has the potential to modulate the expression of genes and function of proteins involved in cell cycle control and DNA damage response pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • BRCA1 Protein / genetics
  • BRCA1 Protein / physiology*
  • CCAAT-Enhancer-Binding Proteins*
  • CDC2-CDC28 Kinases*
  • Cell Cycle / physiology*
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • DNA Damage*
  • DNA-Binding Proteins / genetics
  • Gene Expression / physiology*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / genetics
  • Phosphorylation
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Proteins / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2*
  • Retinoblastoma Protein / metabolism
  • Transcription Factor CHOP
  • Transcription Factors / genetics
  • Tumor Cells, Cultured
  • bcl-2-Associated X Protein

Substances

  • BRCA1 Protein
  • CCAAT-Enhancer-Binding Proteins
  • DDIT3 protein, human
  • DNA-Binding Proteins
  • GADD45 protein
  • Intracellular Signaling Peptides and Proteins
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Retinoblastoma Protein
  • Transcription Factors
  • bcl-2-Associated X Protein
  • Transcription Factor CHOP
  • Protein Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • PIN1 protein, human
  • Peptidylprolyl Isomerase