Programmed cell death, apoptosis, is a critical aspect of normal physiology as well as the genesis and treatment of cancer. Certain apoptotic pathways are transcriptionally regulated;in these cases, apoptosis is induced by the transcriptional activation of genes encoding proapoptotic proteins. This application focuses on the 24p3/24p3R transcriptionally-regulated proapoptotic pathway that our laboratory discovered and has been studying for the past several years. We originally identified 24p3 as the gene undergoing maximum transcriptional stimulation following induction of apoptosis by cytokine-deprivation of interleukin 3 (IL-3) dependent cells. 24p3 is a secreted lipocalin, which we have found induces apoptosis when added to a variety of lymphoid cells. These and other results revealed a model in which IL-3deprivation activates 24p3 transcription, leading to synthesis and secretion of 24p3, which induces apoptosis through an autocrine/paracrine pathway. We have isolated the 24p3 cell surface receptor (24p3R) and found that 24p3 induces apoptosis through a novel pathway culminating in a decrease in intracellular iron levels. The decrease in intracellular iron induces expression of the proapoptotic protein Bim, resulting in apoptosis. Intracellular iron delivery blocks induction of Bim and suppresses apoptosis due to 24p3 addition or IL-3 deprivation. In this application we propose experiments to study the role of the 24p3/24p3R proapoptotic pathway in normal physiology and myeloproliferative disease using cell lines, patient samples and animal models. The basis by which decreased intracellular iron induces apoptosis is not well understood. We will continue to characterize the apoptotic pathway induced by 24p3 and by iron chelators. Expression profiling and RNA interference will be used to identify transcriptionally activated genes involved in 24p3- and iron chelator-mediated apoptosis. Our preliminary results suggest a possible role for the 24p3/24p3R pathway in glucocorticoid-mediated apoptosis and glucocorticoid-resistance, which we will continue to investigate. We have found that the BCR-ABL oncoprotein counteracts the 24p3/24p3R proapoptotic pathway by misregulating expression of 24p3 and 24p3R. These results reveal a new and unanticipated aspect of the mechanism by which BCR-ABL promotes cell survival. We will continue to analyze the generality of this result and study the basis by which 24p3 and 24p3R transcription is misregulated. We have derived 24p3 homozygous knockout mice, which will be used to study the contribution of the 24p3/24p3R proapoptotic pathway to BCR/ABL-induced myeloproliferative disease.
|Wang, Shu-Zong; Ou, Jianhong; Zhu, Lihua J et al. (2012) Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons. Proc Natl Acad Sci U S A 109:18589-94|
|Sheng, Zhi; Ma, Leyuan; Sun, Jiaoyuan E et al. (2011) BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription. Blood 118:2840-8|
|Liu, Zhuoming; Yang, Amy; Wang, Zhengqi et al. (2011) Multiple apoptotic defects in hematopoietic cells from mice lacking lipocalin 24p3. J Biol Chem 286:20606-14|
|Devireddy, Laxminarayana R; Hart, Daniel O; Goetz, David H et al. (2010) A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell 141:1006-17|
|Sheng, Zhi; Evans, Sara K; Green, Michael R (2010) An activating transcription factor 5-mediated survival pathway as a target for cancer therapy? Oncotarget 1:457-60|
|Sheng, Zhi; Li, Li; Zhu, Lihua J et al. (2010) A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications. Nat Med 16:671-7|
|Sheng, Zhi; Wang, Shu-Zong; Green, Michael R (2009) Transcription and signalling pathways involved in BCR-ABL-mediated misregulation of 24p3 and 24p3R. EMBO J 28:866-76|