kdown of NR4A1 decreases TXNDC5 and IDH1 and induced ROS and other stress responses in ACHN and 786-O cells, suggesting that NR4A1 also PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19712481 maintains levels of stress that facilitate RCC HC-030031 web growth and survival. The functions of TXNDC5 and IDH1 have not been characterized in RCC and it is also possible that NR4A1 regulates other similar genes and this is currently being investigated. Since previous studies show that other ROS-inducing antineoplastic agents inhibit growth and survival of RCC, the induction of ROS by C-DIM/NR4A1 antagonists contributed to the anticancer activity of these compounds. mTOR inhibitors are currently in clinical trials for treating RCC, and our previous studies showed that in colon and lung cancer cells expressing wild-type p53, NR4A1 inhibits p53 activity and p53-dependent inhibition of the mTOR pathway. However, treatment with C-DIM/NR4A1 antagonists or transfection with siNR4A1 activates p53 which in turn increases expression of sestrin 2 resulting in activation of AMPK and inhibition of mTOR. These same effects were observed 
in ACHN cells that express wild-type p53, demonstrating that C-DIM/NR4A1 antagonists represent a novel class of mTOR inhibitors with clinical potential for treating RCC patients expressing NR4A1 and wild-type p53. Surprisingly, we also observed similar results in 786-O cells that express a mutant p53, and this response was attenuated by cotreatment with glutathione. Sestrin 2 can be induced by oxidative stress and since NR4A1 knockdown and NR4A1 antagonists induce ROS, this represents a second NR4A1-mediated p53-independent pathway that can be targeted by NR4A1 antagonists to inhibit mTOR. In summary, our results show that NR4A1 is pro-oncogenic in RCC and regulates at least three pathways important for cell proliferation and survival, and these can be targeted by C-DIM/NR4A1 antagonists. Our current studies are focused on further investigating the functional responses and molecular pathways regulated by NR4A1 in RCC and identifying RCC patient sub-types that overexpress NR4A1 and are potential candidates for clinical applications of C-DIM/NR4A1 antagonists. ~~ B cell development is initiated in the bone marrow and can be subdivided into distinct stages based on the expression of surface markers and the recombination status of the 1 / 16 Calponin-3 in B Lymphocyte Development immunoglobulin receptor genes. A major checkpoint is the pre-B cell stage, in which cells that have rearranged the heavy chain gene segments express together with the surrogate light-chain components lambda5/VpreB, forming the pre-B cell receptor . The pre-BCR promotes survival, proliferation and differentiation of pre-B cells into immature B PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19710694 cells, and thus provides a strong selective advantage. Only cells that receive the appropriate signals are able to maturate further, contributing to the mature B cell pool in the periphery. Signaling from the pre-BCR as well as the BCR results in the activation of the tyrosine kinase Syk, which triggers a cascade of downstream events, ultimately resulting in signaling via the PI3K-PKB axis, in release of intracellular calcium and in consequence the activation of effectors such as protein kinase C and transcription factors NF-AT and NF-B. However, although most components in these signaling cascades have been identified in previous efforts, it is tempting to speculate that additional, thus-far unknown proteins may also be functionally relevant. Calponins form an evolutionary highly con
