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A novel mechanism whereby BRCA1/1a/1b fine tunes the dynamic complex interplay between SUMO-dependent/independent activities of Ubc9 on E2-induced ERalpha activation/repression and degradation in breast cancer cells


, : A novel mechanism whereby BRCA1/1a/1b fine tunes the dynamic complex interplay between SUMO-dependent/independent activities of Ubc9 on E2-induced ERalpha activation/repression and degradation in breast cancer cells. International Journal of Oncology 34(4): 939-949

BRCA1 dysfunction is associated with hormone-responsive cancers. We have identified a consensus SUMO modification site in the amino-terminal region of BRCA1/1a/1b proteins and the mutation in this potential SUMO acceptor site (K 109 to R) impaired their ability to bind and repress ligand-dependent ERalpha transcriptional activity in breast cancer cells. Furthermore, we have found SUMO E2-conjugating enzyme Ubc9 to bind BRCA1 proteins. We have mapped BRCA1 [within amino acids (aa) 1-182] as the minimum domain that is sufficient for in vitro binding to Ubc9 as well as for regulating ERalpha activity. BRCA1 Mutant #1 (K109 to R) was impaired in its ability to both bind, as well as modulate Ubc9 mediated SUMO-dependent/independent E2-induced ERalpha transcriptional activity in breast cancer cells. Similarly, BRCA1 cancer-predisposing mutation (61Cys-Gly) abrogated the ability to both bind Ubc9 as well as inhibit ERalpha activity suggesting physiological significance. Addition of BRCA1 but not Mutant #1 to E2-induced ERalpha in the presence of SUMO-1 and Ubc9 resulted in the degradation of ERalpha suggesting BRCA1 to be a putative SUMO-1 and Ubc9-dependent E3 ubiquitin ligase for ERalpha. This is the first report demonstrating the participation of Ubc9 in BRCA1 E3 ubiquitin ligase mediated degradation of ERalpha. These results suggest a novel function for BRCA1 in regulating the dynamic cycles of SUMO and ubiquitin modifications required for ERalpha turn over and deregulation of this molecular switch due to lack of BRCA1 results in ERalpha-negative/positive breast cancers. This study will help in designing novel BRCA1 function-based targeted treatment for breast cancers.

US$29.90

PMID: 19287951


Other references

Bergeron, A.; Nunes, H.; Marchand, E., 2005: Rare and orphan diseases--a national priority. Revue des Maladies Respiratoires 22(6 Pt 1): 919-921

Yasmin, A.; Takeuchi, T.; Hayashi, M.; Hirota, T.; Ishizuka, W.; Ishida, S., 2004: Effect of conjugated linoleic and docosahexaenoic acids on growth of juvenile tilapia Oreochromis niloticus. The present study was conducted to investigate the effects of dietary conjugated linoleic acid (CLA)- and conjugated docosahexaenoic acid (CDHA)-supplemented diets on the growth and body lipid composition of tilapia Oreochromis niloticus. Four die...

Ivanov, V.; Kolodii, N.; Topikha, V., 1975: Utilization of synthetic nitroge. Visnyk sil's'kohospodars'koi nauki: 12 50-53

Calverley, M.H.; Butler, L.J., 1973: Atypical gonadal dysgenesis. A clinical and cytogenetical report of three patients. Journal of Obstetrics and Gynaecology of the British Commonwealth 80(8): 735-744

Yuen, K.Y.; Seto, W.H.; Ong, S.G., 1989: The significance of Branhamella catarrhalis in bronchopulmonary infection: a case-control study. Data, including clinical features of bronchopulmonary infections, i.e. cough with purulent sputum, fever, peripheral blood leucocytosis, patchy pulmonary shadows on chest radiographs and the presence of crepitations or dullness on examination of t...

Munday W.A.Don, 1936: Glaciers of Mount Waddington region. The Canadian Alpine Journal 23

Benvenga, M.J., 2003: Centrally mediated effect of histamine on feeding in female Sprague-Dawley rats. Behavioural Pharmacology 14(Supplement 1): S48, September

Boido, A.; Savelli, F.; Sparatore, F., 1994: Rosmaricine derivatives as potential antitumoral agents. A group of N-(alkylaminoacyl)-O,O-dimethylrosmaricines was prepared and, together with a set of rosmaricine derivatives previously described by us, evaluated for activity against lymphocytic leukemia P 388. Only one compound exhibited a borderline...

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