Our long-term goal is to understand the roles of ribosomal proteins in regulating c-Myc activity during ribosomal biogenesis and in preventing c-Myc-induced cancer formation. In this proposal, we will dissect the L11-c-Myc auto-regulatory feedback loop and its implication in repressing cell transformation. c-Myc promotes cell growth by enhancing ribosomal biogenesis mediated by RNA polymerases I, II and III. Overexpression of c-Myc and aberrant ribosomal biogenesis lead to deregulated cell growth and contribute to tumorigenesis. High levels of c-Myc associate with ~80% of various human cancers. Thus, c-Myc must be tightly controlled in cells. Recently, we have identified ribosomal protein L11, a component of the large subunit of the ribosome, as a likely feedback regulator of c-Myc. L11 is transcriptionally induced by c-Myc. But, overexpression of L11 inhibits c-Myc-dependent transactivation and cell proliferation. L11 directly binds to the Myc box II (MBII) motif within the transactivational domain (TAD) of c-Myc and is recruited to c-Myc target promoters by this transcriptional activator, consequently inhibiting the association of one of the c-Myc coactivators, TRRAP, which also binds to MBII, with c-Myc at these promoters. Furthermore, knockdown of endogenous L11 by siRNA increases c-Myc mRNA and protein levels as well as its activity. Finally, L11 is crucial for the later stage reduction of endogenous c-Myc levels and the late phase inhibition of its activity in response to serum stimulation. In light of these exciting findings, I hypothesize that L11 may act as an auto-regulatory feedback inhibitor of c-Myc, playing a physiological role in negatively regulating c-Myc-enhanced cell proliferation and tumorigenesis. Hence, we will systematically investigate this previously untested hypothesis by addressing three specific aims: (1). Dissect molecular mechanisms underlying L11 inhibition of c-Myc-dependent transcription;(2). Elucidate how L11 regulates c-Myc protein and mRNA levels;(3). Determine the physiological significance of L11-c-Myc inhibitory feedback regulation in cell and animal model systems. These studies will offer new molecular insight into the regulation of c-Myc during ribosomal biogenesis and reveal a potential role of L11 in preventing c-Myc-induced tumorigenesis. Also, these studies will provide important information for developing anti-tumor drugs that inhibit c-Myc and thus are likely useful for treating cancers harboring high levels of active c-Myc.
My proposed studies will offer new molecular insight into the regulation of the c-Myc oncoprotein during de novo protein production, and reveal a potential role of the ribosomal protein L11 in preventing c-Myc-induced cancer formation, as c-Myc is highly expressed in more than 80% of human cancers. Also, these studies will provide important information for developing anti-tumor drugs that inhibit c-Myc and thus are likely useful for treating cancers harboring high levels of active c-Myc.
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