BRCA1 transactivates the cyclin-dependent kinase inhibitor p27(Kip1).
The p27(Kip1) is a member of the universal cyclin-dependent kinase inhibitor family. Previously, immunochemical analysis of a series of breast cancer cell lines demonstrated a correlation between the expression of p27(Kip1) and the breast cancer susceptibility gene BRCA1. BRCA1 has a number of activities including DNA repair, growth inhibition and as a transcription factor. Here we demonstrate that BRCA1 transactivates expression of p27(Kip1). This transactivation is dependent on the presence of a functional C-terminal transactivation domain. Promoter-deletion analysis identified the presence of a putative BRCA1-responsive element located at position -615 to -511 of the p27(Kip1) promoter. These results suggest that the transcriptional regulation of p27(Kip1) by BRCA1 may be a mechanism for BRCA1- induced growth inhibition.
Williamson
Elizabeth A
EA
Department of Medicine, Cedars-Sinai Medical Center, UCLA School of Medicine, 8700 Beverly Blvd., Los Angeles, CA 90048, USA. williamsone@cshs.org
Dadmanesh
Farnaz
F
Koeffler
H Phillip
HP
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D019313:BRCA1 Protein / Q000737:chemistry / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology; D019556:COS Cells / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000473:pathology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D002522:Chlorocebus aethiops; D003110:Colonic Neoplasms / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*
D019313:BRCA1 Protein; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27