Ribosomal proteins L11 and L5 activate TAp73 by overcoming MDM2 inhibition

Abstract

Over the past decade, a number of ribosomal proteins (RPs) have been found to have a role in activating the tumor suppressor p53 by directly binding to MDM2 and impeding its activity toward p53. Herein, we report that RPL5 and RPL11 can also enhance the transcriptional activity of a p53 homolog TAp73, but through a distinct mechanism. Interestingly, even though RPL5 and RPL11 were not shown to bind to p53, they were able to directly associate with the transactivation domain of TAp73 independently of MDM2 in response to RS. This association led to perturbation of the MDM2-TAp73 interaction, consequently preventing MDM2 from its association with TAp73 target gene promoters. Furthermore, ectopic expression of RPL5 or RPL11 markedly induced TAp73 transcriptional activity by antagonizing MDM2 suppression. Conversely, ablation of either of the RPs compromised TAp73 transcriptional activity, as evident by the reduction of p21 and Puma expression, in response to 5-fluorouracil (5-FU). Consistently, overexpression of RPL5 or RPL11 enhanced, but knockdown of either of them hampered, TAp73-mediated apoptosis. Intriguingly, simultaneous knockdown of TAp73 and either of the RPs was required for rescuing the 5-FU-triggered S-phase arrest of p53-null tumor cells. These results demonstrate a novel mechanism underlying the inhibition of tumor cell proliferation and growth by these two RPs via TAp73 activation.

Farnesiferol c induces apoptosis via regulation of L11 and c-Myc with combinational potential with anticancer drugs in non-small-cell lung cancers

“…Among many ribosomal proteins, ribosomal protein L5 or L11 binds to c-Myc8 and also activates TAp73 by overcoming MDM2 inhibition9, consequently leading to inhibition of c-Myc activity. Here, silencing of c-Myc promoted the ability of FC to exert cytotoxicity and sub G1 accumulation in H1299 cells, whereas L11 knockdown abrogated the antitumor activity of FC in H1299 cells.…”

“…Also, c-Myc was known to be regulated by ribosomal biogenesis related proteins, including L11, RPL5 and RPS148910. Especially, L11 was known to act as a novel c-Myc inhibitor8.…”

p73 Regulates Primary Cortical Neuron Metabolism: a Global Metabolic Profile

“…The transcription factor p73 [1-3], a member of the p53-family [4-6], [7,8] exerts its role through the regulation of several biological processes including cell survival [9][10][11], differentiation [12][13][14], cellular metabolism [15][16][17][18][19][20], and autophagy [21]. This pleiotropic role of p73 is mainly due to the fact that the tp73 gene is expressed in numerous isoforms, including two main Nterminal isoforms: a full-length protein named TAp73, and a shorter, N-terminal truncated ΔNp73 isoform.…”

The role of the nucleolus in neurodegeneration.

“…Thus, RPL11 can still potentially modulate p53 in the absence of MDM2 interaction. Additionally, while RPL11 does not directly bind p53, it has been reported to bind TAp73, suggesting this could be a potential alternative mechansism [266]. Moreover, RPL11 is also known to interact with NEDD8 [154].…”

“…Moreover, RPL11 has been demonstrated to have stress related "extra" ribosomal functions independent of its assembly in the 5S RNP and MDM2. Such functions include binding the promoter of p53 target genes and directly binding p73 [266,267].…”