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

Challagundla, Kishore B.; Sun, Xiao Xin; Zhang, Xiaoli; DeVine, Tiffany; Zhang, Qinghong; Sears, Rosalie C.; Dai, Mu Shui

doi:10.1128/mcb.05810-11

Cited by 100 publications

(134 citation statements)

References 74 publications

(128 reference statements)

Supporting

Mentioning

127

Contrasting

Unclassified

Order By: Relevance

“…2 Further interrogating this in a more physiological setting would offer more insight into how these RPs play roles in cancer development and cancer prevention. Because more RPs have been found to activate p53, but inactivate c-Myc, 46,[52][53][54] our findings together with others 28,29 not only strengthen the notion that some RPs, such as RPL5, RPL11 and RPS14, possess intrinsic extra-ribosome functions in regulating other important cancer-relevant protein molecules, but also emphasize their potential roles as tumor suppressors.…”

Section: Discussionsupporting

confidence: 80%

Ribosomal proteins L11 and L5 activate TAp73 by overcoming MDM2 inhibition

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 80%

Ribosomal proteins L11 and L5 activate TAp73 by overcoming MDM2 inhibition

et al. 2014

View full text Add to dashboard Cite

show abstract

“…For example, several ribosomal proteins autoregulate their synthesis by altering splicing or translation of their own mRNA (reviewed in reference 68). Furthermore, L26 binds to the 5= UTR of p53 mRNA, stimulating p53 translation (69), and extraribosomal L11 modulates levels of c-myc by recruiting microRNA (miRNA) and a component of the RNA-induced silencing complex to the 3= UTR of the c-myc gene (70) in response to nucleolar stress. Other ribosomal proteins engage in protein-protein interactions that modulate cellular functions, including those that serve as sentinels to identify states of cellular stress triggered by ribosomal dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Nucleolar Trafficking of the Mouse Mammary Tumor Virus Gag Protein Induced by Interaction with Ribosomal Protein L9

Beyer

Bann

Rice

et al. 2013

J Virol

View full text Add to dashboard Cite

fThe mouse mammary tumor virus (MMTV) Gag protein directs the assembly in the cytoplasm of immature viral capsids, which subsequently bud from the plasma membranes of infected cells. MMTV Gag localizes to discrete cytoplasmic foci in mouse mammary epithelial cells, consistent with the formation of cytosolic capsids. Unexpectedly, we also observed an accumulation of Gag in the nucleoli of infected cells derived from mammary gland tumors. To detect Gag-interacting proteins that might influence its subcellular localization, a yeast two-hybrid screen was performed. Ribosomal protein L9 (RPL9 or L9), an essential component of the large ribosomal subunit and a putative tumor suppressor, was identified as a Gag binding partner. Overexpression of L9 in cells expressing the MMTV(C3H) provirus resulted in specific, robust accumulation of Gag in nucleoli. Förster resonance energy transfer (FRET) and coimmunoprecipitation analyses demonstrated that Gag and L9 interact within the nucleolus, and the CA domain was the major site of interaction. In addition, the isolated NC domain of Gag localized to the nucleolus, suggesting that it contains a nucleolar localization signal (NoLS). To determine whether L9 plays a role in virus assembly, small interfering RNA (siRNA)-mediated knockdown was performed. Although Gag expression was not reduced with L9 knockdown, virus production was significantly impaired. Thus, our data support the hypothesis that efficient MMTV particle assembly is dependent upon the interaction of Gag and L9 in the nucleoli of infected cells. Since its discovery as a milk-transmitted agent in the 1930s, the oncogenic retrovirus mouse mammary tumor virus (MMTV) has served as an important model in breast cancer research and immunology (1). However, little is known about the molecular mechanisms that govern MMTV assembly. The 9-kb MMTV RNA genome consists of the common retroviral elements gag, pro, pol, and env, as well as dut (dUTPase) (2), sag (superantigen) (3), and rem (regulator of export of MMTV mRNA) (4, 5). Like all retroviruses, MMTV uses full-length viral RNA to transcribe the viral structural proteins Gag, Gag-Pro, and Gag-Pro-Pol. The Gag protein directs assembly of complete, immature viral capsids in the cytoplasm, which are subsequently transported to the plasma membrane for release by budding.Unlike acutely transforming retroviruses like Rous sarcoma virus (RSV), MMTV does not carry an oncogene and instead induces tumors primarily by integrating near cellular oncogenes and disrupting their regulation. In addition, the MMTV Gag and Env proteins also promote tumorigenesis independently of the proviral integration site (6, 7). Moreover, differences in pathogenesis between the highly tumorigenic MMTV(C3H) strain and the tumor-attenuated MMTV hybrid provirus (HP) strain map to the CA and NC regions of the Gag protein (6), which led us to hypothesize that the Gag proteins from the C3H and HP strains might differentially interact with cellular proteins to promote malignant transformation.The eukaryotic ribos...

show abstract

“…For instance, both RPL11 and RPS14 were reported to bind the N-terminal MBII domain of c-MYC and avert the binding of the c-MYC coactivator TRRAP [95][96][97], thereby inhibiting c-MYC-mediated transactivation of target genes. Additionally, RPL11 and RPL5 bind the 3 0 UTR of c-MYC mRNA, leading to its microRNA/RISC-mediated degradation [98,99]. Moreover, RPS3 was found to have a dual activity of both enhancing DNA damage repair, thereby contributing to genome stability [100], and mediating apoptosis [101,102].…”

Section: Mechanisms Of P53 Activation Following Ribosome Biogenesis Smentioning

confidence: 99%

p53 and ribosome biogenesis stress: The essentials

2014

View full text Add to dashboard Cite

a b s t r a c tCell proliferation and cell growth are two tightly linked processes, as the proliferation program cannot be executed without proper accumulation of cell mass, otherwise endangering the fate of the two daughter cells. It is therefore not surprising that ribosome biogenesis, a key element in cell growth, is regulated by many cell cycle regulators. This regulation is exerted transcriptionally and post-transcriptionally, in conjunction with numerous intrinsic and extrinsic signals. Those signals eventually converge at the nucleolus, the cellular compartment that is not only responsible for executing the ribosome biogenesis program, but also serves as a regulatory hub, responsible for integrating and transmitting multiple stress signals to the omnipotent cell fate gatekeeper, p53. In this review we discuss when, how and why p53 is activated upon ribosomal biogenesis stress, and how perturbation of this critical regulatory interplay may impact human disease.

show abstract

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

Cited by 100 publications

References 74 publications

Ribosomal proteins L11 and L5 activate TAp73 by overcoming MDM2 inhibition

Ribosomal proteins L11 and L5 activate TAp73 by overcoming MDM2 inhibition

Nucleolar Trafficking of the Mouse Mammary Tumor Virus Gag Protein Induced by Interaction with Ribosomal Protein L9

p53 and ribosome biogenesis stress: The essentials

Contact Info

Product

Resources

About