The Role of mTOR Signaling in the Regulation of RAG Expression and Genomic Stability during B Lymphocyte Development
Annual rept. 15 April 2012 - 14 April 2013
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 past year, we have explored the role of Sin1 in B cell growth and proliferation. These studies identified the pro-growth transcriptional regulator c-Myc as a target of mTORC2 mediated signaling in B cells thereby revealing a novel role for Sin1mTORC2 in B cell growth and metabolic regulation.