The Role of mTOR Signaling in the Regulation of RAG Expression and Genomic Stability During B Lymphocyte Development
Final rept. 15 Apr 2010-14 Apr 2014
YALE UNIV NEW HAVEN CT
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The developing lymphocytes, which are a type of white blood cells, routinely create chromosome breaks while generating unique receptors to recognize foreign pathogens. The enzyme which cuts lymphocyte DNA to facilitate the construction of an immune cell receptor is encoded by two genes collectively known as the recombinase activating genes rags. Expression of the rag genes is tightly controlled by cellular signals that ensure rag is only active in lymphocytes when immune receptor formation is occurring, after which RAG expression is shut down. Our research has revealed that mTOR controls rag expression in B cells by participating in a multi-protein complex called mTOR complex 2 mTORC2. mTORC2 actively inhibits expression of the rag genes in B cells thereby preventing inappropriate rag expression and protecting the B cell DNA from excessive damage caused by rag activity. We found that mTORC2 suppresses rag expression by controlling the activity of a signaling mediator called Akt. Abnormal Akt activity is commonly associated with a wide range of cancers and our research has revealed that mTORC2 plays a key role in controlling Akt activity in B cells raising the possibility that mTORC2 inhibition may be good target for the treatment of certain B cell tumors. We show that inhibition of mTORC2 plus the chaperon protein HSP90 in vitro and in vivo elicits a potent anti-leukemic effect which is greater than inhibiting mTORC2 or HSP90 alone, suggesting that combination of mTOR inhibitors and chaperon inhibition may enhance anti-leukemic activity in blood cancer patients. Over the funding period, we have explored the role of Sin1 in B cell growth and proliferation, either under normal physiological or when become malignant. We have also revealed a combination retreatment for leukemia cells with both mTORC2 inhibitor and molecular chaperon inhibitor.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research