Feedback Control of p53 Translation by REDD1 and mTORC1 Limits the p53-Dependent DNA Damage Response

Vadysirisack, Douangsone D.; Baenke, Franziska; Ory, Benjamin; Lei, Kui; Ellisen, Leif W.

doi:10.1128/mcb.05541-11

Cited by 46 publications

(44 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…mTORC1 can be activated downstream of AKT, and previous studies have suggested mTORC1 can promote p53 protein synthesis. 23,25 However, in our studies the mTORC1 inhibitor rapamycin did not reduce p53 accumulation in Nutlin treated cells (Fig. 3).…”

Section: Discussioncontrasting

confidence: 52%

“…In contrast, we and others found that the IGF-1R/AKT/mTORC1 signaling promotes p53 protein synthesis and maintains p53 expression levels in stressed cells. [22][23][24][25] These findings raise the possibility that heightened IGF-1R/AKT/mTORC1 activation could potentially increase cancer cell sensitivity to Nutlin by maintaining high p53 protein levels. Finally, we recently found the autophagy inhibitors bafilomycin A1 and chloroquine could increase apoptosis sensitivity in Nutlin treated cells, indicating that autophagy promotes apoptosis resistance.…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

The IGF-1R/AKT pathway has opposing effects on Nutlin-3a-induced apoptosis

Davaadelger

Perez

Zhou

et al. 2017

Cancer Biology & Therapy

View full text Add to dashboard Cite

Nutlin-3a is a small molecule MDM2 antagonist and potent activator of wild-type p53. Nutlin-3a disrupts MDM2 binding to p53, thus increasing p53 levels and allowing p53 to inhibit proliferation or induce cell death. Factors that control sensitivity to Nutlin-3a-induced apoptosis are incompletely understood. In this study we isolated cisplatin-resistant clones from MHM cells, an MDM2-amplified and p53 wild-type osteosarcoma cell line. Cisplatin resistance in these clones resulted in part from heightened activation of the IGF-1R/AKT pathway. Interestingly, these cisplatin resistant clones showed hyper-sensitivity to Nutlin-3a induced apoptosis. Increased Nutlin-3a sensitivity was associated with reduced authophagy flux and a greater increase in p53 levels in response to Nutlin-3a treatment. IGF-1R and AKT inhibitors further increased apoptosis by Nutlin-3a in parental MHM cells and the cisplatin-resistant clones, confirming IGF-1R/AKT signaling promotes apoptosis resistance. However, IGF-1R and AKT inhibitors also reduced p53 accumulation in Nutlin-3a treated cells and increased autophagy flux, which we showed can promote apoptosis resistance. We conclude the IGF-1R/AKT pathway has opposing effects on Nutlin-3a-induced apoptosis. First, it can inhibit apoptosis, consistent with its well-established role as a survival-signaling pathway. Second, it can enhance Nutlin-3a induced apoptosis through a combination of maintaining p53 levels and inhibiting pro-survival autophagy.

show abstract

Section: Discussioncontrasting

confidence: 52%

Section: Introductionmentioning

confidence: 97%

The IGF-1R/AKT pathway has opposing effects on Nutlin-3a-induced apoptosis

Davaadelger

Perez

Zhou

et al. 2017

Cancer Biology & Therapy

View full text Add to dashboard Cite

show abstract

“…Recently, it has been reported that DDIT4−/− cells have increased sensitivity to DNA damage in terms of apoptotic response with respect to doxorubicin and radiation, both in vitro and in vivo , in the setting of abnormally increased p53 protein and activity [21]. This could imply that upregulation of DDIT4 would decrease p53 and make cells less sensitive to DNA damage and thus chemotherapy and/or radiation.…”

Section: Discussionmentioning

confidence: 99%

Baicalein upregulates DDIT4 expression which mediates mTOR inhibition and growth inhibition in cancer cells

et al. 2015

View full text Add to dashboard Cite

Baicalein is a natural flavone that exhibits anticancer properties. Using microarrays we found that DDIT4 was the highest transcript induced by baicalein in cancer cells. We confirmed in multiple cancer cell lines large, dose-related expression of DDIT4 by quantitative RT-PCR and immunoblot, which correlates with growth inhibition. Time course experiments demonstrate that DDIT4 is rapidly inducible, with high expression maintained for several days in vitro. Induction of DDIT4 expression is p53 independent based on evaluation of p53 knockout cells. Since DDIT4 is known to inhibit mTORC1 activity we confirmed that baicalein suppresses phosphorylation of mTORC1 targets. Using RNA interference we demonstrate that mTORC1 activity and growth inhibition by baicalein is attenuated by knockdown of DDIT4. We furthermore demonstrate suppression of established tumors by baicalein in a mouse model of breast cancer with increased DDIT4 expression in the tumors. Finally, we demonstrate that baicalein upregulates DDIT4 and causes mTORC1 and growth inhibition in platinum resistant cancer cells in marked contrast to platinum chemotherapy treatment. These studies demonstrate that baicalein inhibits mTORC1 through DDIT4 expression, and may be useful in cancer chemotherapy and chemoprevention.

show abstract

“…One possibility is via mechanistic target of rapamycin (mTOR) kinase, which can be activated by growth signals and regulates mRNA translation via assembly of eukaryotic translation initiation factor (eIF) complex (30). For example, inhibition of mTOR decreases p53 translation (31) whereas knockout of protein regulated in development and DNA damage response 1, a stress-induced inhibitor of mTOR1, increases p53 translation (32). The other possibility is that Ninj1-mediated signals may modulate the assembly of translation initiation complex such as eIF4F complex (4E+4G+4A), eIF4B, and poly(A)-binding protein (33).…”

Section: Lack Of Ninj1 Up-regulates P53 Expression Potentially Throughmentioning

confidence: 99%

Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality

Cho

Rossi

Jung

et al. 2013

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

View full text Add to dashboard Cite

The tumor suppressor protein p53 plays a crucial role in coordinating cellular processes, such as cell cycle arrest, apoptosis, and senescence. The nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a homophilic adhesion molecule and involved in nerve regeneration. Interestingly, Ninj1 is found to be overexpressed in human cancer, but its role in tumorigenesis is not clear. Here, we found that Ninj1 is transcriptionally regulated by p53 and can be induced by DNA damage in a p53-dependent manner. We also found that knockout or knockdown of Ninj1 increases p53 expression potentially through enhanced p53 mRNA translation. In addition, we found that Ninj1 deficiency suppresses cell proliferation but enhances apoptosis and premature senescence in a p53-dependent manner. Consistent with this, we found that mice heterozygous in ninj1 are hypersensitive to ionizing radiation-induced lethality, along with increased expression of p53 in thymus. Taken together, we provided evidence that Ninj1 is a p53 target and modulates p53 mRNA translation and p53-dependent premature senescence, cell proliferation, apoptosis, and radiationinduced mortality in vitro and in vivo. Thus, we postulate that as a membrane adhesion molecule, Ninj1 is an ideal target to regulate p53 activity via the p53-Ninj1 loop. cellular senescence | radiosensitivity

show abstract

Feedback Control of p53 Translation by REDD1 and mTORC1 Limits the p53-Dependent DNA Damage Response

Cited by 46 publications

References 38 publications

The IGF-1R/AKT pathway has opposing effects on Nutlin-3a-induced apoptosis

The IGF-1R/AKT pathway has opposing effects on Nutlin-3a-induced apoptosis

Baicalein upregulates DDIT4 expression which mediates mTOR inhibition and growth inhibition in cancer cells

Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality

Contact Info

Product

Resources

About