The breast cancer tumor-suppressor gene, BRCA1, encodes a protein with a BRCT domain-a motif that is found in many proteins that are implicated in DNA damage response and in genome stability. Phosphorylation of BRCA1 by the DNA damage-response proteins ATM, ATR and hCds1/Chk2 changes in response to DNA damage and at replication-block checkpoints. Although cells that lack BRCA1 have an abnormal response to DNA damage, the exact role of BRCA1 in this process has remained unclear. Here we show that BRCA1 is essential for activating the Chk1 kinase that regulates DNA damage-induced G2/M arrest. Thus, BRCA1 controls the expression, phosphorylation and cellular localization of Cdc25C and Cdc2/cyclin B kinase-proteins that are crucial for the G2/M transition. We show that BRCA1 regulates the expression of both Wee1 kinase, an inhibitor of Cdc2/cyclin B kinase, and the 14-3-3 family of proteins that sequesters phosphorylated Cdc25C and Cdc2/cyclin B kinase in the cytoplasm. We conclude that BRCA1 regulates key effectors that control the G2/M checkpoint and is therefore involved in regulating the onset of mitosis.
Germ-line mutations in the BRCA1 tumorsuppressor gene are associated with an increased susceptibility to breast and ovarian cancer. BRCA1 contains a carboxylterminal domain (BRCT) that is shared with several other proteins involved in maintaining genome integrity. In an effort to understand the function of BRCA1, we sought to isolate proteins that interact with the BRCT domain. Purified BRCT polypeptide was used as a probe to screen a human placenta cDNA expression library by Far Western analysis. Here we report that BRCA1 interacts in vivo and in vitro with the Rb-binding proteins, RbAp46 and RbAp48, as well as with Rb. Moreover, the BRCT domain associates with the histone deacetylases HDAC1 and HDAC2. These results demonstrate that BRCA1 interacts with components of the histone deacetylase complex, and therefore may explain the involvement of BRCA1 in multiple processes such as transcription, DNA repair, and recombination.More than half of families with inherited breast and ovarian cancer susceptibility are thought to harbor germ-line mutations in the BRCA1 gene. Frequent loss of the wild-type allele in tumors of mutation carriers suggests that BRCA1 acts as a tumor-suppressor gene. Surprisingly, mutations in BRCA1 in sporadic breast and ovarian cancer are extremely rare (1-3). To date, more than 600 different mutations in the BRCA1 gene have been reported (Breast Cancer Information Core: www. nhgri.nih.gov͞Intramuralresearch͞Labtransfer͞Bic͞). The majority of these are truncation mutations distributed over the entire length of the gene. Several missense mutations have also been shown to segregate with cancer susceptibility (1, 4, 5).The BRCA1 gene was isolated and mapped to human chromosome 17q21 (6). The gene encodes an 1,863-aa protein with an apparent molecular mass of 220 kDa. Only a few conserved sequence motifs have been identified in the BRCA1 protein: an amino-terminal RING finger, a carboxyl-terminal region that contains two repeats of a newly identified motif, designated BRCT (BRCA1 carboxyl terminus) domain (7), and three nuclear localization signals in the central portion of the molecule (8). However, much of the biochemical function of BRCA1 is unknown.BRCA1 is found in nuclear foci that form in a cell cycledependent manner (9, 10). Several lines of evidence suggest that BRCA1 expression is cell cycle regulated and plays a role in cell cycle checkpoints. BRCA1 mRNA is highly expressed during embryonic development and is increased in breast epithelia during pregnancy and in adult testis during the final stages of meiosis and spermatogenesis (11, 12), suggesting a role in terminal differentiation. Brca1Ϫ͞Ϫ mouse embryos die early in development from cell proliferation defects, including cell cycle arrest (13,14). In human cell lines, BRCA1 expression suppresses cell growth (15)(16)(17). The presence of the BRCT motif in BRCA1 also links it to cell cycle control. Many other cell cycle checkpoint proteins, such as the p53-binding protein (53BP1), fission yeast replication checkpoint proteins,...
Strigolactones are a novel class of plant hormones produced in roots and regulate shoot and root development. We have previously shown that synthetic strigolactone analogues potently inhibit growth of breast cancer cells and breast cancer stem cells. Here we show that strigolactone analogues inhibit the growth and survival of an array of cancer-derived cell lines representing solid and non-solid cancer cells including: prostate, colon, lung, melanoma, osteosarcoma and leukemic cell lines, while normal cells were minimally affected. Treatment of cancer cells with strigolactone analogues was hallmarked by activation of the stress-related MAPKs: p38 and JNK and induction of stress-related genes; cell cycle arrest and apoptosis evident by increased percentages of cells in the sub-G1 fraction and Annexin V staining. In addition, we tested the response of patient-matched conditionally reprogrammed primary prostate normal and cancer cells. The tumor cells exhibited significantly higher sensitivity to the two most potent SL analogues with increased apoptosis confirmed by PARP1 cleavage compared to their normal counterpart cells. Thus, Strigolactone analogues are promising candidates for anticancer therapy by their ability to specifically induce cell cycle arrest, cellular stress and apoptosis in tumor cells with minimal effects on growth and survival of normal cells.
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