Inhibition of c-Myc activity by ribosomal protein L11.
The c-Myc oncoprotein promotes cell growth by enhancing ribosomal biogenesis through upregulation of RNA polymerases I-, II-, and III-dependent transcription. Overexpression of c-Myc and aberrant ribosomal biogenesis leads to deregulated cell growth and tumorigenesis. Hence, c-Myc activity and ribosomal biogenesis must be regulated in cells. Here, we show that ribosomal protein L11, a component of the large subunit of the ribosome, controls c-Myc function through a negative feedback mechanism. L11 is transcriptionally induced by c-Myc, and overexpression of L11 inhibits c-Myc-induced transcription and cell proliferation. Conversely, reduction of endogenous L11 by siRNA increases these c-Myc activities. Mechanistically, L11 binds to the Myc box II (MB II), inhibits the recruitment of the coactivator TRRAP, and reduces histone H4 acetylation at c-Myc target gene promoters. In response to serum stimulation or serum starvation, L11 and TRRAP display inverse promoter-binding profiles. In addition, L11 regulates c-Myc levels. These results identify L11 as a feedback inhibitor of c-Myc and suggest a novel role for L11 in regulating c-Myc-enhanced ribosomal biogenesis.
Dai
Mu-Shui
MS
Department of Biochemistry and Molecular Biology, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USA.
Arnold
Hugh
H
Sun
Xiao-Xin
XX
Sears
Rosalie
R
Lu
Hua
H
D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D015870:Gene Expression; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012269:Ribosomal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016196:S Phase; D044967:Serum; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D000097796:Nucleolin
D048868:Adaptor Proteins, Signal Transducing; D006657:Histones; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; D000097796:Nucleolin; C027624:ribosomal protein L11; C035078:ribosomal protein L29; C113829:transformation-transcription domain-associated protein