This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Apoptosis is a fundamental process in metazoan development. It is a central component of countless events during animal development that serve to sculpt and shape structures, eliminate obsolete tissues, and closely control cell number. Apoptosis also plays a critical role throughout the life of an organism for the maintenance of tissue architecture and homeostasis. Defects in apoptosis are associated with a several debilitating conditions including cancer, autoimmune disorders, and neurodegenerative diseases. An in-depth understanding of the mechanisms and regulation of apoptosis is central to the development of new, more effective therapies for these conditions. We propose to advance understanding of apoptotic mechanisms through study of the recently identified Drosophila morgue gene. morgue encodes an F-box protein that suppresses levels of Drosophila IAP-1 (DIAP1) to promote apoptosis in developing tissues. Our preliminary findings have shown Morgue to be a key regulator of mitochondrial membrane depolarization during apoptosis, and to be required for organelle breakdown and cell surface phosphatidylserine display. Loss of Morgue results in failure to commit to apoptosis and prolonged survival of corpse-like cells in vivo. Thus, proper regulation of Morgue activity is central to the progression of apoptosis in Drosophila.
The specific aims of this project are to a) characterize the influence of sumoylation and phosphorylation on Morgue activity, and b) characterize additional genes required for PS display and organelle breakdown. We will use a multidisciplinary approach to these experiments that will include classical genetic studies, as well as molecular and biochemical approaches.
|Subramanian, Chitra; Grogan, Patrick T; Opipari, Valerie P et al. (2018) Novel natural withanolides induce apoptosis and inhibit migration of neuroblastoma cells through down regulation of N-myc and suppression of Akt/mTOR/NF-?B activation. Oncotarget 9:14509-14523|
|Ishiguro, Susumu; Kawabata, Atsushi; Zulbaran-Rojas, Alejandro et al. (2018) Co-treatment with a C1B5 peptide of protein kinase C? and a low dose of gemcitabine strongly attenuated pancreatic cancer growth in mice through T cell activation. Biochem Biophys Res Commun 495:962-968|
|He, Chenchen; Duan, Shaofeng; Dong, Liang et al. (2017) Characterization of a novel p110?-specific inhibitor BL140 that overcomes MDV3100-resistance in castration-resistant prostate cancer cells. Prostate 77:1187-1198|
|White, Peter T; Subramanian, Chitra; Zhu, Qing et al. (2016) Novel HSP90 inhibitors effectively target functions of thyroid cancer stem cell preventing migration and invasion. Surgery 159:142-51|
|Ohta, Naomi; Ishiguro, Susumu; Kawabata, Atsushi et al. (2015) Human umbilical cord matrix mesenchymal stem cells suppress the growth of breast cancer by expression of tumor suppressor genes. PLoS One 10:e0123756|
|Li, Benyi; Thrasher, James Brantley; Terranova, Paul (2015) Glycogen synthase kinase-3: a potential preventive target for prostate cancer management. Urol Oncol 33:456-63|
|Ishiguro, Susumu; Yoshimura, Kiyoshi; Tsunedomi, Ryouichi et al. (2015) Involvement of angiotensin II type 2 receptor (AT2R) signaling in human pancreatic ductal adenocarcinoma (PDAC): a novel AT2R agonist effectively attenuates growth of PDAC grafts in mice. Cancer Biol Ther 16:307-16|
|Li, Benyi; Sun, Aijing; Jiang, Wencong et al. (2014) PI-3 kinase p110?: a therapeutic target in advanced prostate cancers. Am J Clin Exp Urol 2:188-98|
|Bibis, Stergios S; Dahlstrom, Kelly; Zhu, Tongtong et al. (2014) Characterization of Leishmania major phosphatidylethanolamine methyltransferases LmjPEM1 and LmjPEM2 and their inhibition by choline analogs. Mol Biochem Parasitol 196:90-9|
|Subramanian, Chitra; Zhang, Huaping; Gallagher, Robert et al. (2014) Withanolides are potent novel targeted therapeutic agents against adrenocortical carcinomas. World J Surg 38:1343-52|
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