Regulation of Mitogenesis in Health and in Disease

Ponce School Of Medicine, Ponce PR

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Abstract

Description (provided by applicant): Cancer, atherosclerosis, and pulmonary fibrosis, are now among the most important diseases for which we need efficient prevention and control. In spite of the widely appreciated magnitude of this problem, the mechanisms of abnormal mitogenesis remain undetermined. While promotion of mitogenesis by growth factors and hydrogen peroxide (H2O2), a second messenger of mitogenic signaling, are well established, little is known of negative regulators that restrict mitogenesis. Catalase, a H2O2 scavenger, acts as a negative regulator of mitogenesis, yet a possibility of regulatory alteration of catalase activity for control of mitogenesis remains unexplored. Our preliminary data suggest that PKA and PKC-zeta activators upregulate catalase activity and suppress mitogenic growth of several cell lines. We also found that tyrosine phosphorylation of catalase binds Grb2, an adaptor protein of cell signaling, and that catalase contains a consensus sequence of "suppressor of cytokine signaling" (SC-motif 1). Therefore, we hypothesize that catalase is capable of binding signaling molecules and elongin C, an essential factor for elongation in RNA synthesis, and that this binding along with signaling by PKA, PKC-zeta and protein tyrosine kinase alter H2O2 scavenging activity and RNA synthesis to control H2O2-dependent mitogenesis. Thus understanding the regulatory mechanisms of catalase for control of mitogenesis should provide new strategies for the suppression of abnormal mitogenesis. To prove this hypothesis the following aims are proposed; Aim 1: To determine the mechanism responsible for PKA and PKC-zeta-dependent up-regulation of catalase activity that suppress mitogenesis. Aim 2: To determine the roles of a sequence equivalent to SC-motif 1 within catalase to bind a molecule that regulates catalase activity and mitogenesis. Aim 3: To determine the mechanisms responsible for PTK-dependent down-regulation of catalase activity and the binding of catalase to signaling molecules that promote a mitogenic signaling. This study postulates a novel and innovative concept that catalase activity is modulated by cell-signaling-, and intermolecular association-dependent mechanism. This research allows to establish how catalase, PKA and PKC-zeta activators are commonly able to act as negative regulators of cell mitogenesis, (1) by identifying critical molecules for modulation of catalase activity, (2) by determining the effects of PKA and PKC-zeta signaling on catalase activity, and (3) by determining the ability of catalase to bind signaling molecules and elongin C which contribute to regulate mitogenic signaling and RNA synthesis.