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Postdoctoral Training, Yale University
Ph.D., Andhra University
MS, Andhra University
Function Based Therapeutic Strategies to Human cancers (Functionotherapeutics): Study of the Functional Role of ETS-fusion genes in Prostate cancer, Ewing Sarcoma, Breast Cancer and Leukemias
We have discovered and cloned several oncogenes and studied their functions (close to twenty genes). The most notable genes discovered include ERG-1 and ERG-2 genes (we have named the gene as ETS Related Gene). This gene is involved in 40-80% of Prostate cancers, Ewing sarcoma and also leukemias (AML). Other notable genes discovered and studied by Dr Reddy include human Fli-1 (involved in Leukemias), EWS-Fli-1 (involved in Ewing Sarcoma) , EWS-erg (involved in Ewing Sarcoma), TLS-erg (involved in Acute Myeloid Leukemia), EWS (involved in multiple cancers), TLS/FUS (involved in multiple cancers), ELK-1 (ETS Like Gene), BRCA2a (involved in breast, ovarian and prostate cancers) and EWS-ATF-1 (involved in malignant Melanoma of Soft Parts). We have identified the DNA binding, trans-activation domains and other regulatory domains of ERG, ELK-1, Fli-1, EWS-Fli-1, EWS-erg, TLS-erg, EWS-ATF-1, BRCA2a etc. We have successfully targeted EWS-fusion proteins and shown that this approach can be used as a therapy for Ewing family of tumors. Dr Reddy and his colleagues are identifying the function of these oncogenes and also developing strategies to target these oncoproteins or their functions to develop novel targeted therapeutic agents. Using this Function based therapeutic strategy, we have developed several novel drugs (patent being submitted) that target Prostate, Ewing Sarcoma, Breast cancer (triple negative breast cancer), Pancreatic cancer, Ovarian, cervical cancers, and colorectal cancers.
We have recently discovered novel post-translational mechanism that will have global effect on the gene expression, differentiation, protein turnover, cell death, cancer and other Human diseases. Majority of N-linked glycosylation of proteins occurs 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 independent of this protein translocation (Science,314, 1148, 2006). Here, Dr Reddy and his group find that such protein modifications (protein translocation-independent N-glycosylation) can also occur even in eukaryotic cells. They show that transcriptional cofactor CBP interacts with BRCA2 protein (involved in breast cancer, ovarian cancer and prostate cancer) 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 (PTING).
Dr Reddy predicts that this CBP/p300-mediated post-translational modification may be a signal for degradation/turnover of CBP interacting proteins. Interestingly, BRCA2 protein is known to be ubiquitinated and degraded by the proteosomal pathway. Dr Reddy is presently testing this hypothesis. Since CBP/p300 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.
- Cancer Biology of Prostate cancer, Ewing Sarcoma, Leukemias, Breast cancer
- Function Based therapeutic strategies of cancers, Posttranslational modifications of proteins
- Protein homeostasis, Pancreatic cancer, Ovarian cancer
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