mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Dominick, Graham; Bowman, Jacqueline; Li, Xinna; Miller, Richard A.; Garcia, Gonzalo G.

doi:10.1111/acel.12525

Cited by 50 publications

(58 citation statements)

References 54 publications

(88 reference statements)

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“…Based on our results and other research data we can postulate that a post transcriptional modification may be achieved by NDRG1 interaction with the HSP90 protein (53). The mTOR signaling pathway may also be involved, since the downstream regulator CCR4-NOT may upregulate NDRG1 (54,55). Such post transcriptional regulation may act along with post translational modification, such as e.g.…”

Section: Discussionsupporting

confidence: 63%

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

et al. 2017

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Abstract. N-myc downstream-regulated gene 1 (NDRG1) is a tumor suppressor with the potential to suppress metastasis, invasion and migration of cancer cells. It is regulated under stress conditions such as starvation or hypoxia. NDRG1 regulation is both induced and controlled by HIF-1α-dependent and -independent pathways under hypoxic conditions. However, there are profound differences in the way NDRG1 expression is regulated by HIF-1α and other transcription factors. Therefore, we aimed to define the time-dependent pattern of NDRG1 mRNA and protein expression in human glioblastoma cell lines in extreme hypoxia and after re-oxygenation as well as under normoxic conditions. Furthermore, we ascribe the regulation of NDRG1 to the transcription factors HIF-1α, SP1, CEBPα, YB-1 and Smad7 in a time-dependent manner. The human malignant glioma cell lines U87-MG, U373 and GaMG were cultured for 1, 6 and 24 h under hypoxic (0.1% O 2 ) conditions and then they were re-oxygenated. The mRNA expression of NDRG1, HIF-1α SP1, CEBPα, YB-1 and Smad7 was measured using semi-quantitative RT-PCR analysis. Their protein expression was analyzed using western blotting. Our experiments revealed that long-term (24 h), but not short-term hypoxia led to the induction of NDRG1 expression in human glioma cell lines. NDRG1 expression was found to correlate with the protein expression of HIF-1α, SP1, CEBPα, YB-1 and Smad7. The present study suggests for the first time that SP1 regulates NDRG1 expression in glioma cells under hypoxia in a time-dependent manner along with HIF-1α, CEBPα, YB-1 and Smad7. These molecules, each separately or in combination, may possess the potential to become target molecules for antitumor therapeutic approaches particularly in human brain tumors.

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Section: Discussionsupporting

confidence: 63%

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

et al. 2017

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“…Modulation of mTOR activity suppresses proteins that are involved in chromosomal integrity and enhances DNA damage–induced apoptosis in cancer cells (31, 32), whereas the deletion of mTOR causes a defective DDR in mitotic cells (33). More recently, DDR factors were demonstrated to be up‐regulated via post‐transcriptional mechanism in 3 genetic mouse models with the mTORC1 pathway attenuated (34).…”

mentioning

confidence: 99%

Conditional ablation of Raptor in the male germline causes infertility due to meiotic arrest and impaired inactivation of sex chromosomes

et al. 2017

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Rapamycin is a clinically important drug that is used in transplantation and cancer therapy but which causes a number of side effects, including male infertility. Its canonical target, mammalian target of rapamycin complex 1 (mTORC1), plays a key role in metabolism and binds chromatin; however, its precise role in the male germline has not been elucidated. Here, we inactivate the core component, Raptor, to show that mTORC1 function is critical for male meiosis and the inactivation of sex chromosomes. Disruption of the gene impairs chromosomal synapsis and prevents the efficient spreading of silencing factors into the XY chromatin. Accordingly, mRNA for XY-linked genes remains inappropriately expressed in-deficient mice. Molecularly, the failure to suppress gene expression corresponded with deficiencies in 2 repressive chromatin markers, H3K9 dimethylation and H3K9 trimethylation, in the XY body. Together, these results demonstrate that mTORC1 has an essential role in the meiotic progression and silencing of sex chromosomes in the male germline, which may explain the infertility that has been associated with such inhibitors as rapamycin.-Xiong, M., Zhu, Z., Tian, S., Zhu, R., Bai, S., Fu, K., Davis, J. G., Sun, Z., Baur, J. A., Zheng, K., Ye, L. Conditional ablation of in the male germline causes infertility due to meiotic arrest and impaired inactivation of sex chromosomes.

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“…Furthermore, mTORC1-dependent phosphorylation of the transcription factor TFEB promotes association of TFEB with members of the 14-3-3 family of proteins, thereby forcing its retention in the cytosol (88). However, the network connecting the mTOR pathway to the DNA damage response continues to be elucidated (92)(93)(94)(95). A recent study (95) showed that mTOR/S6K signaling leads to phosphorylation and subsequent degradation of RNF168, and hyperactivation of mTOR via LKB1 leads to decreased levels of RNF168 and increases DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance

Temprine¹,

Langdon

Mehta

et al. 2018

Preprint

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AbstractMutations in the proofreading domains of the replicative DNA polymerases polδ and polε are associated with elevated mutation rates in cancer, but the roles of other DNA polymerases in tumorigenesis remain poorly understood. One such polymerase is polκ, an enzyme that plays a key role in translesion synthesis. polκ contributes to cell survival in the face of DNA damage but can be highly mutagenic due to lack of a proofreading domain. Here we demonstrate that cancer cells under stress from oncogene inhibition upregulate polκ and shift its localization from the cytoplasm to the nucleus. This effect can be phenocopied by mTOR inhibition or glucose deprivation, analogous to stress-induced mutagenesis in E. coli whereby cell stress and nutrient deprivation can upregulate and activate DinB/pol IV (the bacterial orthologue of polκ). We find that cancer cells normally sequester polκ in the cytoplasm via exportin-1, likely to prevent excess mutagenesis from the error-prone nature of this polymerase. Subverting the normal nuclear-cytoplasmic shuttling by forced overexpression of nuclear polκ increases resistance of melanoma cells to the BRAFV600E inhibitor vemurafenib. This data suggests a mechanism by which cancer cells regulate the expression and localization of the error-prone polymerase polκ, abrogation of which can contribute to drug resistance.One Sentence Summary: Cancer cells under stress from oncogene or mTOR inhibition dysregulate the error-prone DNA polymerase polκ, which contributes to drug resistance in melanoma cells.

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mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Cited by 50 publications

References 54 publications

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

Conditional ablation of Raptor in the male germline causes infertility due to meiotic arrest and impaired inactivation of sex chromosomes

Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance

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