Research Interests
Chromatin remodeling complexes play a key role in the regulation of cellular transcription by modulating access of proteins to DNA. In human neoplasia, alterations in components of chromatin remodeling complexes can impact many hallmarks of human cancers including cell cycle regulation, cellular differentiation, DNA methylation, imprinting and gene transcription. Several recent reports have demonstrated loss of function of components of the SWI/SNF (mating type switch/sucrose nonfermenting) chromatin remodeling complex in human and mouse cancers. Absence of the SWI2 homologue, BRG1, leads to a loss of the RB tumor suppressor protein's ability to control the cell cycle. Loss of SNF5/INI1/BAF47 function underlies the development of most rhabdoid tumors. Our laboratory has found that over 20% of human adenocarcinoma cell lines have lost expression of at least one member of the SWI/SNF complex. We have also found mutations and deletions of the SNF5 gene in human rhabdoid tumor cell lines and primary rhabdomyosarcomas. How the loss of different components of the SWI/SNF complex contributes to neoplastic transformation remains an open and important question. My laboratory concentrates on addressing this question by the combined use of biological, biochemical and mouse models for SWI/SNF complex function. We have focused our efforts on four components of complex including BRG1, BRM, BAF57 and SNF5/INI1. We hypothesize that alterations in the activities of components of the SWI/SNF complex contribute to human and mouse tumor development by altering the regulation of key cell cycle components. We are testing this hypothesis by determining the mechanisms underlying BAF57- and SNF5-induced inhibition of growth upon re-expression in deficient human tumor cell lines. Our data have shown that loss of snf5 function inactivates expression of the p16INK4A gene. We are also carrying out structure/function analyses of these proteins as well as BRG1 and BRM by biological and biochemical assays. We are also assessing the consequences of the loss of the snf5 gene on a mouse model for choroid plexus carcinomas. Altered SWI/SNF function could impact upon several aspects of human tumor etiology. For example, we have shown that the SWI/SNF complex regulates CD44 expression. Loss of CD44 expression in human tumors often correlates with poorer prognosis. SWI/SNF complex loss may render tumor cells resistant to the lethal effects of cis-platinum. Therefore, loss of SWI/SNF function may negatively impact treatment modalities used for the spread of metastatic adenocarcinomas and may provide an informative indicator of therapeutic progress. Finally, considering that the SWI/SNF complex acts as a global regulator of transcription, human tumors that lose its function may possess a greater likelihood for progression and metastases due to a higher potential for altered gene expression.

Strobeck, M.W., Knudsen, K.E., Fribourg, A.F., DeCristofaro, M.F., Weissman, B.E., Imbalzano, A.N. and Knudsen, E.S. BRG-1 is required for RB mediated cell cycle arrest. Proc. Nat. Acad. Sci., USA., 2000 97:7748-7753.

Reisman, D. N., Strobeck, M.W., Betz, B.L., Sciariotta, J., Funkhouser, W. Jr., Murchardt, C., Yaniv, M., Sherman, L.S., Knudsen, E.S. and Weissman, B.E. Concomitant down-regulation of BRM and BRG1 in human tumor cell lines: Differential effects on RB-mediated growth arrest vs. CD44 expression. Oncogene, 2002 21:1196-1207.

Strobeck, M.W., Reisman, D, Gunawardena, R., Betz, B.L., Angus, S. P., Knudsen, K. E., Kowalik, T., Weissman, B. E. and Knudsen, E. S. Compensation of BRG-1 function by Brm: Insight into the role of the core SWI/SNF subunits in cancer. J. Biol. Chem., 2002 277:4782-4789.

Betz, B.L., Strobeck, M.W., Reisman, D.N., Knudsen, E.S. and Weissman, B.E. Reexpression of hSNF5/INI1 in pediatric tumor cells leads to G1 arrest associated with induction of p16ink4a and activation of RB. Oncogene. 2002 21:5193-5203.

Recent Accomplishments and Honors
My laboratory has identified a potential mechanism for regulation of the cell cycle by the SWI/SNF complex. We have shown that reexpression of the snf5/ini1 component of the complex in deficient cell lines leads to
a cell cycle arrest through the induction of p16ink4a. We have also shown that loss of expression of the key members of the SWI/SNF complex, BRG1 and BRM, occurs frequently in human tumor cell lines and to a lesser degree in human non-small cell lung carcinomas (NSCLC).
Importantly, loss of these components correlated with poor overall survival in these patients. Therefore, BRG1/BRM loss may provide a novel prognostic marker for patients with NSCLC.

Publications
DeCristofaro, M. F., Betz, B. L., Wang, W. and Weissman, B.E.
Alteration of hSNF5/INI1/BAF47 Detected in Rhabdoid Cell Lines and
Primary Rhadbomyosarcomas but not Wilms' Tumors. Oncogene. 1999,
18:7559-7565.

Strobeck, M.W., Knudsen, K.E., Fribourg, A.F., DeCristofaro, M.F.,
Weissman, B.E., Imbalzano, A.N. and Knudsen, E.S. BRG-1 is required for
RB mediated cell cycle arrest. Proc. Nat. Acad. Sci., USA., 2000
97:7748-7753.

Reisman, D. N., Strobeck, M.W., Betz, B.L., Sciariotta, J., Funkhouser,
W. Jr., Murchardt, C., Yaniv, M., Sherman, L.S., Knudsen, E.S. and
Weissman, B.E. Concomitant down-regulation of BRM and BRG1 in human
tumor cell lines: Differential effects on RB-mediated growth arrest vs.
CD44 expression. Oncogene, 2002 21:1196-1207.

Betz, B.L., Strobeck, M.W., Reisman, D.N., Knudsen, E.S. and Weissman,
B.E. Reexpression of hSNF5/INI1 in pediatric tumor cells leads to G1
arrest associated with induction of p16ink4a and activation of RB.
Oncogene. 2002 21:5193-5203.

Reisman, D.N., Sciarrota, J., Wang, W., Funkhouser, W.K., and Weissman,
B.E. Loss of BRG1/BRM in human lung cancer cell lines and primary
tumors: Correlation with poor prognosis. Cancer Research, 2003 63:560-566.

E-mail: weissman@med.unc.edu
Telephone: (919) 966-7533 / 1350
FAX: (919) 966-9673
Address: 32-048 Lineberger Chapel Hill, NC
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