HuR stabilizes TFAM mRNA in an ATM/p38‐dependent manner in ionizing irradiated cancer cells

Zhang, Rui; Wang, Jun

doi:10.1111/cas.13657

Cited by 24 publications

(22 citation statements)

References 42 publications

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“…TFAM is a regulator of mitochondrial biogenesis and plays an important role in the maintenance of mitochondrial DNA integrity and mitochondrial functions. It has been reported that inhibition of TFAM led to increased sensitivity of cancer cells to cisplatin, doxorubicin, or ionizing irradiation [26,27]. Mitochondrial dysfunctions could result in variations of autophagy.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of TFAM in Tumor Cells Retarded Autophagic Flux through Regulating p53 Acetylation and PISD Expression

Jiang

Wang

2020

Cancers

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Mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA replication and transcription, which are essential for mitochondrial biogenesis. Previous studies reported that depleting mitochondrial functions by genetic deletion of TFAM impaired autophagic activities. However, the underlying mechanisms remain largely unknown. In the current study, we identified that knockdown of TFAM repressed the synthesis of autophagy bio-marker LC3-II in tumor cells and decreased the expression of phosphatidyl-serine decarboxylase (PISD). Besides, downregulation of PISD with siRNA reduced the level of LC3-II, indicating that depletion of TFAM retarded autophagy via inhibiting PISD expression. Furthermore, it was found that the tumor repressor p53 could stimulate the transcription and expression of PISD by binding the PISD enhancer. Additionally, the protein stability and transcriptional activity of p53 in TFAM knockdown tumor cells was attenuated, and this was associated with decreased acetylation, especially the acetylation of lysine 382 of p53. Finally, we identified that TFAM knockdown increased the NAD+/NADH ratio in tumor cells. This led to the upregulation of Sirtuin1 (SIRT1), a NAD-dependent protein deacetylase, to deacetylate p53 and attenuated its transcriptional activation on PISD. In summary, our study discovered a new mechanism regarding disturbed autophagy in tumor cells with mitochondrial dysfunction due to the depletion of TFAM.

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Section: Discussionmentioning

confidence: 99%

Knockdown of TFAM in Tumor Cells Retarded Autophagic Flux through Regulating p53 Acetylation and PISD Expression

Jiang

Wang

2020

Cancers

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“…Total DNA was extracted from the parental XTC.UC1, XTC.UC1/MIEAP, and XTC.UC1/PARK2 cells using DNeasy Blood & Tissue Kit (Qiagen). Quantitative PCR according to the ΔΔCt method was carried out as described previously 27,28 . 12S rDNA encoded by mtDNA and β‐actin encoded by nDNA were quantified, and the mtDNA / nDNA ratio was used to estimate the relative mtDNA copy number, ie the relative amounts of mitochondria.…”

Section: Methodsmentioning

confidence: 99%

Causative role for defective expression of mitochondria‐eating protein in accumulation of mitochondria in thyroid oncocytic cell tumors

et al. 2020

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Oncocytic cell tumor of the thyroid is composed of large polygonal cells with eosinophilic cytoplasm that is rich in mitochondria. These tumors frequently have the mutations in mitochondrial DNA encoding the mitochondrial electron transport system complex I. However, the mechanism for accumulation of abnormal mitochondria is unknown. A noncanonical mitophagy system has recently been identified, and mitochondria‐eating protein (MIEAP) plays a key role in this system. We therefore hypothesized that accumulation of abnormal mitochondria could be attributed to defective MIEAP expression in these tumors. We first show that MIEAP was expressed in all the conventional thyroid follicular adenomas (FAs)/adenomatous goiters (AGs) but not in oncocytic FAs/AGs; its expression was defective not only in oncocytic thyroid cancers but also in the majority of conventional thyroid cancers. Expression of MIEAP was not correlated with methylation status of the 5′‐UTR of the gene. Our functional analysis showed that exogenously induced MIEAP, but not PARK2, reduced the amounts of abnormal mitochondria, as indicated by decreased reactive oxygen species levels, mitochondrial DNA / nuclear DNA ratios, and cytoplasmic acidification. Therefore, together with previous studies showing that impaired mitochondrial function triggers compensatory mitochondrial biogenesis that causes an increase in the amounts of mitochondria, we conclude that, in oncocytic cell tumors of the thyroid, increased abnormal mitochondria cannot be efficiently eliminated because of a loss of MIEAP expression, ie impaired MIEAP‐mediated noncanonical mitophagy.

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“…In addition, the TFAM mRNA is subject to complex post-transcriptional regulation ( Figure 4 ), including stabilization by RNA-binding proteins [ 226 ] and various microRNAs [ 227 , 228 , 229 , 230 ]. For example, microRNA-494 (mir494) was shown to downregulate TFAM expression in proliferating myoblasts by binding to 3′-UTR within the mRNA sequence.…”

Section: Regulation Of Mthmg Proteinsmentioning

confidence: 99%

Mitochondrial HMG-Box Containing Proteins: From Biochemical Properties to the Roles in Human Diseases

et al. 2020

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Mitochondrial DNA (mtDNA) molecules are packaged into compact nucleo-protein structures called mitochondrial nucleoids (mt-nucleoids). Their compaction is mediated in part by high-mobility group (HMG)-box containing proteins (mtHMG proteins), whose additional roles include the protection of mtDNA against damage, the regulation of gene expression and the segregation of mtDNA into daughter organelles. The molecular mechanisms underlying these functions have been identified through extensive biochemical, genetic, and structural studies, particularly on yeast (Abf2) and mammalian mitochondrial transcription factor A (TFAM) mtHMG proteins. The aim of this paper is to provide a comprehensive overview of the biochemical properties of mtHMG proteins, the structural basis of their interaction with DNA, their roles in various mtDNA transactions, and the evolutionary trajectories leading to their rapid diversification. We also describe how defects in the maintenance of mtDNA in cells with dysfunctional mtHMG proteins lead to different pathologies at the cellular and organismal level.

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HuR stabilizes TFAM mRNA in an ATM/p38‐dependent manner in ionizing irradiated cancer cells

Cited by 24 publications

References 42 publications

Knockdown of TFAM in Tumor Cells Retarded Autophagic Flux through Regulating p53 Acetylation and PISD Expression

Knockdown of TFAM in Tumor Cells Retarded Autophagic Flux through Regulating p53 Acetylation and PISD Expression

Causative role for defective expression of mitochondria‐eating protein in accumulation of mitochondria in thyroid oncocytic cell tumors

Mitochondrial HMG-Box Containing Proteins: From Biochemical Properties to the Roles in Human Diseases

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