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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| Zhou, X; Hao, Q; Zhang, Q et al. (2015) Ribosomal proteins L11 and L5 activate TAp73 by overcoming MDM2 inhibition. Cell Death Differ 22:755-66 |
| Liao, J-M; Zhou, X; Gatignol, A et al. (2014) Ribosomal proteins L5 and L11 co-operatively inactivate c-Myc via RNA-induced silencing complex. Oncogene 33:4916-23 |
| He, Guifen; Zhang, Yi-Wei; Lee, Jun-Ho et al. (2014) AMP-activated protein kinase induces p53 by phosphorylating MDMX and inhibiting its activity. Mol Cell Biol 34:148-57 |
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| Zhang, Qi; Zeng, Shelya X; Lu, Hua (2014) Targeting p53-MDM2-MDMX loop for cancer therapy. Subcell Biochem 85:281-319 |
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| Nakhoul, Hani; Ke, Jiangwei; Zhou, Xiang et al. (2014) Ribosomopathies: mechanisms of disease. Clin Med Insights Blood Disord 7:7-16 |
| Zhan, Yang; Cao, Bo; Qi, Yanfeng et al. (2013) Methylselenol prodrug enhances MDV3100 efficacy for treatment of castration-resistant prostate cancer. Int J Cancer 133:2225-33 |
| Liao, Jun-Ming; Lu, Hua (2013) ChIP for identification of p53 responsive DNA promoters. Methods Mol Biol 962:201-10 |
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