Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1.

Somasundaram K,
Zhang H,
Zeng YX,
Houvras Y,
Peng Y,
Zhang H,
Wu GS,
Licht JD,
Weber BL,
El-Deiry WS

Laboratory of Molecular Oncology and Cell Cycle Regulation,

Howard Hughes Medical Institute,
Department of Medicine,
University of Pennsylvania
School of Medicine,
Philadelphia 19104, USA.

Much of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in the BRCA1 tumour-suppressor gene.

The nuclear protein BRCA1 has the properties of a transcription factor, and can interact with the recombination and repair protein RAD51.

Young women with germline alterations in BRCA1 develop breast cancer at rates 100-fold higher than the general population, and BRCA1-null mice die before day 8 of development.

However, the mechanisms of BRCA1-mediated growth regulation and tumour suppression remain unknown.

Here we show that BRCA1 transactivates expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in a p53-independent manner.

BRCA1 inhibits cell-cycle progression into the S-phase following its transfection into human cancer cells.

BRCA1 does not inhibit S-phase progression in p21-/- cells, unlike p21+/+ cells

Tumour-associated, transactivation-deficient mutants of BRCA1 are defective in both transactivation of p21 and cell-cycle inhibition.

These data suggest that one mechanism by which BRCA1 contributes to cell-cycle arrest and growth suppression is through the induction of p21.

MeSH Terms:
Animal
BRCA1 Protein/physiology*
BRCA1 Protein/genetics
Cell Cycle/physiology*
Cell Cycle/genetics
Cyclin-Dependent Kinases/metabolism
Cyclins/physiology*
Cyclins/genetics
COS Cells
DNA/biosynthesis
Enzyme Inhibitors/pharmacology
Gene Expression Regulation
Genes, Suppressor, Tumor
Hela Cells
Human
Luminescent Proteins
Mice
Mutation
Promoter Regions (Genetics)
Support, Non-U.S. Gov't
Support, U.S. Gov't, P.H.S.
Trans-Activation (Genetics)
Transfection
Tumor Cells, Cultured

Substances:
DNA
green fluorescent protein
Luminescent Proteins
Enzyme Inhibitors
Cyclins
Cyclin-Dependent Kinases
Cip1 protein
BRCA1 Protein

PMID: 9296497, UI: 97441059