Feedback Regulation of c-Myc by Ribosomal Protein L11

Abstract

Several ribosomal proteins including L11 have been shown to activate p53 by inhibiting oncoprotein MDM2, leading to inhibition of cell cycle progression. Our recent study showed that L11 also inhibits oncoprotein c-Myc. Overexpression of L11 inhibits c-Myc-induced transcription and cell proliferation, while reduction of endogenous L11 increases these c-Myc activities. Interestingly, L11 is a transcriptional target of c-Myc, thus forming a negative feedback loop. We further showed that L11 competes with co-activator TRRAP for binding to c-Myc through the Myc box II (MB II) and reduces histone H4 acetylation at c-Myc target gene promoters. In addition, L11 appears to regulate c-Myc levels. Knocking down L11 markedly increases the mRNA and protein levels of endogenous c-Myc. These results suggest that L11 also inhibits cell cycle progression by regulating the c-Myc pathway. Here we further discuss the implications of this regulation and questions that this finding raises.

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

“…Subsequently, increased rpL11 will be also involved in the p53 activation and negatively regulate the level of c-myc. This supposition is the same as the previous report, which RPL11 acts as a feedback regulator of c-Myc (Dai et al, 2007). In Figure 4d, rpL11 knockdown partly decreased the p53 level in the aberrant ribosome biogenesis.…”

Ribosomal Protein S14 Negatively Regulates c-Myc Activity

“…However, it remains intriguing to explore their extra-ribosomal functions in the p53-indepentent pathway. RPL11 was recently found to not only inhibit c-Myc transcriptional activity by directly binding to its MBII domain (37,47), but also suppress c-Myc mRNA expression via a miRNA-mediated mechanism (38). It remains possible that RPL11 might not be the only ribosomal protein that regulates c-Myc activity and stability, given that nearly a dozen of ribosomal proteins, including RPL11, RPL5 RPL23, RPS7, and RPS14, have been shown to play a role in regulation of the MDM2-p53 pathway (48 -55).…”

Ribosomal Protein L11 Recruits miR-24/miRISC To Repress c-Myc Expression in Response to Ribosomal Stress

“…We have also found that L11 regulates c-Myc levels (12,15). However, the underlying mechanism is not clear.…”

“…Knockdown of L11 drastically increased the levels of c-Myc protein (12) (bottom panels of Fig. 1A) and c-myc mRNA (15) in U2OS cells. RT-qPCR assays revealed that the levels of c-myc mRNA were markedly increased upon knockdown of L11 (top panel of Fig.…”