Jeong Keun Rih | PubMed Health

PubMed2005

BRCA1 regulates gene expression for orderly mitotic progression.

Germline mutations of the BRCA1 gene confer an increased risk for breast cancer and ovarian cancer. To study the contribution of BRCA1 to sporadic cancers, which often exhibit reduced BRCA1 expression, we tested the effect of knocking down BRCA1 on gene expression in human prostate (DU-145) and breast (MCF-7) cancer cells. DNA microarray and confirmatory RNA analyses revealed that BRCA1 small interfering (si) RNA caused down-regulation of multiple genes implicated in the mitotic spindle checkpoint (eg., BUB1B, HEC, and STK6), chromosome segregation (eg., ESPL1, NEK2, and PTTG1), centrosome function (eg., ASPM), cytokinesis (eg., PRC1, PLK, and KNSL2), and the progression into and through mitosis (eg., CDC2, and CDC20). Cells treated with BRCA1-siRNA showed attenuation of the mitotic spindle checkpoint; but not several G2 checkpoints. Finally, BRCA1 knockdown caused the accumulation of multinucleated cells, suggesting a defect in cytokinesis. We conclude that BRCA1 regulates gene expression for orderly mitotic progression.

BRCA1 Protein↗

PubMed2004

BRCA1 induces antioxidant gene expression and resistance to oxidative stress.

Mutations of the breast cancer susceptibility gene 1 (BRCA1), a tumor suppressor, confer an increased risk for breast, ovarian, and prostate cancers. To investigate the function of the BRCA1 gene, we performed DNA microarray and confirmatory reverse transcription-PCR analyses to identify BRCA1-regulated gene expression changes. We found that BRCA1 up-regulates the expression of multiple genes involved in the cytoprotective antioxidant response, including glutathione S-transferases, oxidoreductases, and other antioxidant genes. Consistent with these findings, BRCA1 overexpression conferred resistance while BRCA1 deficiency conferred sensitivity to several different oxidizing agents (hydrogen peroxide and paraquat). In addition, in the setting of oxidative stress (due to hydrogen peroxide), BRCA1 shifted the cellular redox balance to a higher ratio of reduced to oxidized glutathione. Finally, BRCA1 stimulated antioxidant response element-driven transcriptional activity and enhanced the activity of the antioxidant response transcription factor nuclear factor erythroid-derived 2 like 2 [also called NRF2 (NFE2L2)]. The ability of BRCA1 to stimulate antioxidant response element-dependent transcription and to protect cells against oxidative stress was attenuated by inhibition of nuclear factor erythroid-derived 2 like 2. These findings suggest a novel function for BRCA1, i.e., to protect cells against oxidative stress. This function would be consistent with the postulated role of BRCA1 as a caretaker gene in preserving genomic integrity.

Antioxidants↗