The c-Myc oncoprotein is a cellular target of great interest because its proper physiological level is essential for normal cell growth and proliferation, while its deregulated overexpression is closely related to many human cancers. Thus c-Myc level and activity must be tightly controlled in cells. In an attempt to understand the regulation of c-Myc, I have recently identified that ribosomal protein L11, a component of the large subunit of the ribosome, inhibits c-Myc transactivation activity and induction of cell proliferation. As L11 is transcriptionally induced by c-Myc, these results lead to an important hypothesis that L11 may act as a critical auto-regulatory feedback inhibitor of c-Myc. My current research focuses on understanding this L11-c-Myc feedback inhibition by further characterizing L11-c-Myc protein-protein interaction, L11 protein-c-myc mRNA interaction, and the inhibitory effect of L11 on c-Myc-enhanced ribosomal biogenesis. ? My broad, long-term objectives of this application in the independent phase are to study how L11 inhibits c-Myc function and whether L11 suppresses c-Myc's transformation activity in cells and oncogenic activity in vivo.
Three specific aims are proposed: 1) To investigate the mechanisms underlying the inhibitory role of L11 on c-Myc activity, I will analyze whether L11 conceals c-Myc transactivation domain on its target gene promoters; 2) To investigate whether L11 regulates c-myc mRNA level and translation through microRNA-guided pathways, I will investigate whether L11 binds to 3'-UTR of c-myc mRNA with RNA interference silencing complex (RISC) to degrade c-myc mRNA and/or silence its translation; 3) To investigate the physiological significance of the inhibitory effect of L11 on c-Myc, I will determine whether L11-c-Myc loop plays a role in normal cellular growth response and also in response to certain types of cellular stress, and whether L11 suppresses c-Myc-induced transformation in cells and tumor formation in mice. ? Achieving these aims from this project using biochemical, cellular and molecular biological, and genetic approaches would demonstrate a novel tumor suppressive function of L11 by inhibiting c-Myc. Since ablating c-Myc expression leads to regression of c-Myc-induced tumors in multiple tissues, results from the mechanistic studies on L11's inhibitory effect on c-Myc would offer useful information for developing antitumor drugs that target c-Myc in cancer patients. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K99)
Project #
5K99CA127134-02
Application #
7491554
Study Section
Special Emphasis Panel (ZCA1-RTRB-2 (J1))
Program Officer
Lohrey, Nancy
Project Start
2007-09-01
Project End
2009-03-31
Budget Start
2008-09-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$39,645
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Li, Yuhuang; Challagundla, Kishore B; Sun, Xiao-Xin et al. (2015) MicroRNA-130a associates with ribosomal protein L11 to suppress c-Myc expression in response to UV irradiation. Oncotarget 6:1101-14
Dai, Mu-Shui; Challagundla, Kishore B; Sun, Xiao-Xin et al. (2012) Physical and functional interaction between ribosomal protein L11 and the tumor suppressor ARF. J Biol Chem 287:17120-9
Sun, Xiao-Xin; Challagundla, Kishore B; Dai, Mu-Shui (2012) Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1. EMBO J 31:576-92
Dai, Mu-Shui; Lu, Hua (2008) Crosstalk between c-Myc and ribosome in ribosomal biogenesis and cancer. J Cell Biochem 105:670-7
Dai, Mu-Shui; Sun, Xiao-Xin; Lu, Hua (2008) Aberrant expression of nucleostemin activates p53 and induces cell cycle arrest via inhibition of MDM2. Mol Cell Biol 28:4365-76
Sun, Xiao-Xin; Dai, Mu-Shui; Lu, Hua (2008) Mycophenolic acid activation of p53 requires ribosomal proteins L5 and L11. J Biol Chem 283:12387-92
Dai, Mu-Shui; Sears, Rosalie; Lu, Hua (2007) Feedback regulation of c-Myc by ribosomal protein L11. Cell Cycle 6:2735-41