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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA129828-05
Application #
8247175
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Spalholz, Barbara A
Project Start
2008-07-01
Project End
2014-04-30
Budget Start
2012-06-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$302,919
Indirect Cost
$101,644
Name
Tulane University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Lo, D; Zhang, Y; Dai, M-S et al. (2015) Nucleostemin stabilizes ARF by inhibiting the ubiquitin ligase ULF. Oncogene 34:1688-97
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
Zhang, Qi; Zhou, Xiang; Wu, RuiZhi et al. (2014) The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress. Elife 3:
Liao, Jun-Ming; Cao, Bo; Zhou, Xiang et al. (2014) New insights into p53 functions through its target microRNAs. J Mol Cell Biol 6:206-13
Liao, Jun-Ming; Lu, Hua (2013) ChIP for identification of p53 responsive DNA promoters. Methods Mol Biol 962:201-10
Zhang, Yiwei; Zhang, Qi; Zeng, Shelya X et al. (2013) Inauhzin sensitizes p53-dependent cytotoxicity and tumor suppression of chemotherapeutic agents. Neoplasia 15:523-34
Zhou, Xiang; Hao, Qian; Liao, Jun-Ming et al. (2013) Ribosomal protein S14 negatively regulates c-Myc activity. J Biol Chem 288:21793-801
Liao, Jun-Ming; Zhang, Yu; Liao, Wenjuan et al. (2013) I*B kinase * (IKK*) inhibits p63 isoform ýý (TAp63ýý) transcriptional activity. J Biol Chem 288:18184-93
Goeman, Frauke; Fontemaggi, Giulia; Blandino, Giovanni (2013) ChIP-on-chip to identify mutant p53 targets. Methods Mol Biol 962:211-26
Zhou, X; Hao, Q; Liao, J et al. (2013) Ribosomal protein S14 unties the MDM2-p53 loop upon ribosomal stress. Oncogene 32:388-96

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