AKT Promotes rRNA Synthesis and Cooperates with c-MYC to Stimulate Ribosome Biogenesis in Cancer

Chan, Joanna C.; Hannan, Katherine M.; Riddell, Kim; Ng, Pui Yee; Peck, Abigail; Lee, Rachel S.; Hung, Stevephen; Astle, Megan V.; Bywater, Megan J.; Wall, Meaghan; Poortinga, Gretchen; Jastrzebski, Katarzyna; Sheppard, Karen E.; Hemmings, Brian A.; Hall, Michael N.; Johnstone, Ricky W.; McArthur, Grant A.; Hannan, Ross D.; Pearson, Richard B.

doi:10.1126/scisignal.2001754

Cited by 127 publications

(145 citation statements)

References 68 publications

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“…The stimulatory effect of activated Akt on rRNA synthesis was, until recently, thought to be mediated by the mammalian target of rapamycin (mTOR). However, recent data have demonstrated that inhibition of mTOR activity by rapamycin has little effect on rRNA synthesis, although sustained inhibition of both Akt and mTOR markedly suppress both rRNA synthesis and ribosome biogenesis by limiting RNA polymerase I (Pol I) loading onto DNA and by reducing pre-rRNA processing (3). These observations support the view that Akt may play a critical role in controlling ribosomal biogenesis, but the mechanism by which it does so has not been defined.…”

supporting

confidence: 72%

“…Although cellular transformation has been most frequently related to the dysregulation of protein translation as a consequence of mTOR activation (35,36), the role of Akt in enhancing ribosomal biogenesis is receiving increasing attention (3,37). The up-regulation of rRNA synthesis is a prerequisite for all tumors and presents a unique opportunity for therapeutic intervention (38).…”

Section: Discussionmentioning

confidence: 99%

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Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA

Nguyen

Mitchell

2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Ribosomal proteins are synthesized in the nucleolus under the control of a number of repetitive DNA elements and are required for cell proliferation. Cancer cells frequently contain mutations that activate the phosphoinositide 3-kinase/Akt signaling pathway. This study shows that activation of Akt enhances the transcription of ribosomal genes by stabilizing a protein, transcription initiation factor I (TIF-IA), which is essential for the transcription of ribosomal DNA. Activated Akt also increases ribosomal RNA synthesis by phosphorylating casein kinase 2, which in turn phosphorylates and enhances the activity of TIF-IA. These results demonstrate new mechanisms by which the activation of Akt can promote tumor cell proliferation and further support the targeting of activated Akt as a potential therapy for certain cancers.

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supporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA

Nguyen

Mitchell

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, increased rRNA transcription and ribosomal biogenesis were observed in cancers subject to c-Myc activation (17,18). To this end, we therefore examined the protein concentrations and cell proliferation in MDA-MB-231 cells with HSPC111/RTCD1 knockdown.…”

Section: Attenuated Protein Synthesis Upon Hspc111 and Rtcd1 Reductionmentioning

confidence: 99%

“…Enhanced rRNA synthesis and ribosomal biogenesis are commonly seen in human cancers coupled with resultant protein translation and cell-proliferation acceleration (17)(18)(19). The effect of c-Myc on driving cell growth is in part due to its role in transcribing rDNA and advancing ribosomal biogenesis (20).…”

Section: Introductionmentioning

confidence: 99%

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

Zhang

Yin

Wang

et al. 2014

Molecular Cancer Research

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Activation of c-Myc plays a decisive role in the development of many human cancers. As a transcription factor, cMyc facilitates cell growth and proliferation by directly transcribing a multitude of targets, including rRNAs and ribosome proteins. However, how to elucidate the deregulation of rRNAs and ribosome proteins driven by c-Myc in cancer remains a significant challenge and thus warrants close investigation. In this report, a crucial role for the HSPC111 (NOP16) multiprotein complex in governing ribosomal biogenesis and tumor growth was determined. It was discovered that enhanced HSPC111 expression paralleled the upregulation of c-Myc and was directly regulated by c-Myc in breast cancer cells. Knockdown of HSPC111 dramatically reduced the occurrence of tumorigenesis in vivo, and largely restrained tumor cell growth in vitro and in vivo. In stark contrast, HSPC111 overexpression significantly promoted tumor cell growth. Biochemically, it was demonstrated that RNA 3 0 -phosphate cyclase (RTCD1/RTCA) interacted with HSPC111, and RTCD1 was involved in the HSPC111 multiprotein complex in regulating rRNA production and ribosomal biogenesis. Moreover, HSPC111 and RTCD1 synergistically modulated cell growth and cellular size through commanding rRNA synthesis and ribosome assembly coupled to protein production. Finally, overall survival analysis revealed that concomitant upregulation of HSPC111 and RTCD1 correlated with the worst prognosis in a breast cancer cohort.Implications: Inhibition of HSPC111-dependent ribosomal biosynthesis and protein synthesis is a promising therapeutic strategy to diminish breast cancer tumor progression. Mol Cancer Res; 12(4); 583-94. Ó2014 AACR. IntroductionBreast cancer is by far the most common cancer among women and the leading cause of cancer-related deaths worldwide. The primary tumor and metastases to distant organs often cause significant morbidity and mortality. Numerous studies suggest that the oncogene c-Myc plays a crucial role in the development and progression of breast cancer. Along with its partner protein Max, c-Myc regulates an estimated 10% to 15% of genes in the human genome, and globally reprograms cells and drives proliferation (1-3). Aberrant regulation and overexpression of c-Myc are observed in most tumor types,

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“…The PI3K-AKT-mTOR and RAS pathways cooperate with MYC to control ribosome biogenesis and protein synthesis in normal and malignant cells (20,21), with the PI3K-AKTmTOR pathway in particular regulating ribosome biogenesis and function at multiple steps. PI3K-AKT-mTOR signaling controls rRNA synthesis at the levels of rDNA transcription and rRNA processing as well as RP synthesis by regulating translation initiation for 5′ terminal oligopyrimidine (TOP)-containing mRNAs (20,(22)(23)(24). PI3K-AKT-mTOR signaling modulates mRNA translation at both the initiation and elongation stages, including the promotion of eIF4E-dependent 5′ CAP-dependent translation initiation (20,21,23,25,26).…”

Section: Research Briefmentioning

confidence: 99%

Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma

et al. 2016

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Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I-mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K-AKT-mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYCdriven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eμ-Myc lymphoma-bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies. SIGNIFICANCE:Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eμ-Myc lymphoma-bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer. Cancer Discov; 6(1);[59][60][61][62][63][64][65][66][67][68][69][70]

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AKT Promotes rRNA Synthesis and Cooperates with c-MYC to Stimulate Ribosome Biogenesis in Cancer

Cited by 127 publications

References 68 publications

Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA

Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma

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