EXCEED THE SPACE PROVIDED. Normal aerobic metabolism is associated with the generation of reactive oxygen species (ROS). Certain forms of ROS, such as hydrogen peroxide (H202), function as intracellular second messengers. ROS, however, also cause damage to DNA, proteins and lipids. Aerobic cells cope with the generation of potentially toxic ROS through antioxidant defense mechanisms. For example, catalase, a heine-containing peroxisomal enzyme, catalyzes the conversion of H202 to water and oxygen. H202 is also converted to water by cytosolic and mitochondrial glutathione peroxidase in a reaction which oxidizes glutathione. Despite the importance of these enzymes in controlling ROS, few insights are available regarding the regulation of catalase or glutathione peroxidase activity. Moreover, while failure of these and other antioxidant defenses to control ROS-induced damage is associated with apoptosis, little is known about the mechanisms that determine cell fate in response to oxidative stress. The c-Abl and related Arg nonreceptor tyrosine kinases are activated in the cellular response to oxidative stress. Activation of c-Abl is associated with targeting of c-Abl to mitochondria, release of cytochrome c and induction of apoptosis. Activation of Arg contributes to ROS-induced apoptosis by a mechanism involving tyrosine phosphorylation of the pro-apoptotic Siva-1 protein. The finding that cells deficient in c-Abl or Arg exhibit an attenuated apoptotic response to oxidative stress has supported a mechanism involving both proteins. Our hypothesis is that c-Abl and Arg form heterodimers in the ROS response and that this complex is of importance to the regulation of catalase and glutathione peroxidase. Moreover, our hypothesis is that, if these enzymatic antioxidant mechanisms are unable to control ROS-induced damage, then c-Abl and Arg function as a switch to signal apoptosis. The proposed studies will address these hypotheses and how c-Abl and Arg determine cell fate in the oxidative stress response.
The Specific Aims are: 1) To further define the mechanisms responsible for activation of c-Abl and Arg signaling in response to oxidative stress; 2) To determine the role of c-Abl and Arg in the regulation of oxidative stress by catalase; 3) To assess the effects of c-Abl and Arg on activation of glutathione peroxidase; and 4) To define the downstream effectors of c-Abl and Arg in the apoptotic response to oxidative stress. PERFORMANCE SITE ========================================Section End===========================================

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemical Pathology Study Section (CPA)
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Yang, Shen K
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Dana-Farber Cancer Institute
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Agata, Naoki; Ahmad, Rehan; Kawano, Takeshi et al. (2008) MUC1 oncoprotein blocks death receptor-mediated apoptosis by inhibiting recruitment of caspase-8. Cancer Res 68:6136-44
Ahmad, Rehan; Raina, Deepak; Meyer, Colin et al. (2008) Triterpenoid CDDO-methyl ester inhibits the Janus-activated kinase-1 (JAK1)-->signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3. Cancer Res 68:2920-6
Yin, Li; Kharbanda, Surender; Kufe, Donald (2007) Mucin 1 oncoprotein blocks hypoxia-inducible factor 1alpha activation in a survival response to hypoxia. J Biol Chem 282:257-66
Ahmad, Rehan; Raina, Deepak; Meyer, Colin et al. (2006) Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179. J Biol Chem 281:35764-9
Yoshida, Kiyotsugu; Yamaguchi, Tomoko; Natsume, Tohru et al. (2005) JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage. Nat Cell Biol 7:278-85
Agata, Naoki; Nogi, Hiroko; Bamberg, Michael et al. (2005) The angiogenesis inhibitor NM-3 is active against human NSCLC xenografts alone and in combination with docetaxel. Cancer Chemother Pharmacol 56:610-4
Cao, Cheng; Li, Yanping; Leng, Yumei et al. (2005) Ubiquitination and degradation of the Arg tyrosine kinase is regulated by oxidative stress. Oncogene 24:2433-40
Yin, Li; Huang, Lei; Kufe, Donald (2004) MUC1 oncoprotein activates the FOXO3a transcription factor in a survival response to oxidative stress. J Biol Chem 279:45721-7
Cao, Cheng; Leng, Yumei; Liu, Xuan et al. (2003) Catalase is regulated by ubiquitination and proteosomal degradation. Role of the c-Abl and Arg tyrosine kinases. Biochemistry 42:10348-53
Yin, Li; Li, Yongqing; Ren, Jian et al. (2003) Human MUC1 carcinoma antigen regulates intracellular oxidant levels and the apoptotic response to oxidative stress. J Biol Chem 278:35458-64