Functionotherapeutics: Gene Discovery and Function based Therapeutic Strategies

MSM Cancer Biologists Discover Novel Post-Translational Mechanism and Possible Implications on Gene Expression, Cancer and Other Human Diseases

Morehouse School of Medicine (MSM) researchers have discovered a novel post-translational mechanism that will have global effect on the gene expression, differentiation, cancer and other human diseases.

 Shyam Reddy, Ph.D., professor and co-director, Cancer Biology Program, and Georgia Cancer Coalition distinguished cancer scholar, and his group have shown for the first time transcription factor CBP-mediated post-translational N-glycosylation of BRCA2 protein (involved in breast, ovarian and prostate cancers) (International Journal of Oncology 35: 387-391, 2009).

The majority of N-linked glycosylation of proteins occur in secretory and membrane proteins. This typical N-glycosylation of a protein takes place upon entry of the protein into the lumen of endoplasmic reticulum (ER), where there is a transfer of carbohydrate moiety to asparagine residue present in the protein. In bacteria, N-glycosylation can occur independently of the protein traslocation. Here, Reddy and his group find that such protein modifications can also occur even in eukaryotic cells. They show that transcriptional cofactor CBP interacts with BRCA2 protein and mediates its N-glycosylation both in vitro and in vivo. This is the first report that a transcription cofactor like CBP may be involved in protein translocation-independent N-glycosylation.

Reddy predicts that this CBP-mediated post-translational modification may be a signal for regulation of stability of CBP interacting proteins. Interestingly, BRCA2 protein is known to be ubiquitinated and degraded by the proteosomal pathway. Reddy is presently testing this hypothesis. Since CBP cofactor interacts with many onco-proteins, tumor suppressors and transcription factors, such a signal may be vital to regulate the expression of these interacting proteins which play an important role in cell growth, differentiation and cell death.

Therefore, this post-translational N-glycosylation can have global effect on gene function, cell growth and differentiation. Micro deletions, chromosomal translocations and point mutations in CBP are linked to congenital developmental disorder, Rubinstein-Taybi syndrome (RTS), neurogenerative diseases and cancer. It is possible that deregulation of CBP-mediated glycosyltransferase is associated with development of RTS, neurogenerative diseases, and cancers.

Other researchers participating in this study include Veena N Rao, Ph.D., professor and co-director of the Cancer Biology Program and Georgia Cancer Coalition distinguished cancer scholar; Habibur Siddique, Ph.D.

This work was funded by Georgia Cancer Coalition Distinguished Cancer Scholar Award to Reddy and Rao, MSM/UAB/TU U54 partnership, NIH RO1 and DOD grant awards to Reddy.