Advisory Committee Chair
Danny Welch
Advisory Committee Members
Andra Frost
Robert Hardy
Coral Lamartiniere
Joanne Murphy-Ullrich
Document Type
Dissertation
Date of Award
2008
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
BRMS1 and SUDS3 belong to a protein family characterized by the Sds3-like domain. These proteins are core members of SIN3-HDAC chromatin remodeling complexes and thus, regulate transcription. BRMS1 decreases the expression of various metastasis-promoting proteins. This regulation contributes to BRMS1-mediated metastasis suppression through the inhibition of motility and by sensitizing cells to anoikis, as well as through other unidentified mechanisms related to growth at a secondary site. Although BRMS1 and SUDS3 share high sequence similarity and are found in the same complexes, studies have yet to address whether these similarities result in overlapping functions. Additionally, it is unclear how BRMS1 and SUDS3 interact with each other and with SIN3-HDAC complexes to affect transcription. The studies presented here were undertaken to characterize BRMS1 and SUDS3 as family members and, moreover, to define their interaction. We therefore sought to determine if SUDS3 over-expression could compensate for BRMS1 deficiency in breast cancer cells. We found SUDS3, unlike BRMS1, to be present in all breast cancer cell lines regardless of metastatic potential. Further, SUDS3 iv over-expression could not compensate for BRMS1 deficiency to effect metastasis suppression, decreased motility, increased anoikis, or decreased EGFR, OPN, and activated Akt. We also sought to characterize the region of BRMS1 necessary for interaction with SUDS3. Mutational studies showed the first coiled-coil domain of BRMS1 to be necessary but not sufficient for interaction with SUDS3 and that a predicted imperfect leucine-zipper does not play a role in this interaction. These studies increase the knowledge of the Sds3-like protein family by defining distinct, non-overlapping functions for BRMS1 and SUDS3 in breast cancer cells. Further, they contribute to the understanding of protein-protein interactions involved in the composition of SIN3-HDAC complexes by suggesting that BRMS1 and SUDS3 serve distinct functions within these complexes and by further defining how these two proteins interact. By understanding the role of this protein family and how these SIN3-HDAC complexes are assembled, we can begin to elucidate the normal roles of these proteins and complexes and further, how they are involved in pathological processes, especially metastasis.
Recommended Citation
Silveira, Alexandra C., "Characterization of SUDS3 as a BRMS1 Family member in Breast Cancer" (2008). All ETDs from UAB. 302.
https://digitalcommons.library.uab.edu/etd-collection/302