p53 increase mitochondrial copy number via up-regulation of mitochondrial transcription factor A in colorectal cancer

Wen, Shilei; Gao, Jinhang; Zhang, Linhao; Zhou, Hongying; Fang, Dingzhi; Shi, Feng

doi:10.18632/oncotarget.12514

Cited by 31 publications

(31 citation statements)

References 35 publications

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“…P53 is involved in regulation of the cycle arrest, apoptosis and senescence . It not only interacts with the promotor of TFAM to activate TFAM transcription but also binds with TFAM to regulate cell death . However, whether TFAM can influence p53 has not been identified.…”

Section: Introductionmentioning

confidence: 99%

Down‐regulation of TFAM increases the sensitivity of tumour cells to radiation via p53/TIGAR signalling pathway

Jiang

Wang

2019

J Cellular Molecular Medi

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Mitochondrial transcription factor A (TFAM) is a key regulator of mitochondria biogenesis. Previous studies confirmed that reduced TFAM expression sensitized tumours cells to chemical therapy reagents and ionizing irradiation (IR). However, the underlying mechanisms remain largely unknown. In this study, we identified that decreased expression of TFAM impaired the proliferation of tumour cells by inducing G1/S phase arrest and reducing the expression of E2F1, phospo‐Rb, PCNA and TK1. Furthermore, we proved that knockdown of TFAM enhanced the interaction between p53 and MDM2, resulting in decreased expression of p53 and the downstream target TIGAR, and thus leading to elevated level of mitochondrial superoxide and DNA double‐strand break (DSB) which were exacerbated when treated the cell with ionizing radiation. Those indicated that knockdown of TFAM could aggravate radiation induced DSB levels through affecting the production of mitochondria derived reactive oxygen species. Our current work proposed a new mechanism that TFAM through p53/TIGAR signalling to regulate the sensitivity of tumour cells to ionizing radiation. This indicated that TFAM might be a potential target for increasing the sensitization of cancer cells to radiotherapy.

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Section: Introductionmentioning

confidence: 99%

Down‐regulation of TFAM increases the sensitivity of tumour cells to radiation via p53/TIGAR signalling pathway

Jiang

Wang

2019

J Cellular Molecular Medi

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“…TFAM is reported to be associated with tumorigenesis in breast, cervical, prostate, small cell lung cancers [12][13][14][15][16]. Also, frequent frameshift mutations in the coding mononucleotide repeat of TFAM was demonstrated in sporadic CRC derived cell lines and CRC tissues [17,18]. Previous study suggested that the reduced mtDNA copy number increased the sensitivity of tumor cells to chemotherapeutic drugs, suggesting that TFAM could be a potential contributor for tumor progression [19].…”

Section: Introductionmentioning

confidence: 99%

Down-Regulation of MicroRNA-214 Contributed to the Enhanced Mitochondrial Transcription Factor A and Inhibited Proliferation of Colorectal Cancer Cells

Zhan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Colon cancer, also known as colorectal cancer (CRC), is one of the most common malignant tumors globally. Although significant advances have been made for developing novel therapeutics, the mechanisms of progression of colorectal cancer are still poorly understood. Methods: In this study, we identified down-regulation of microRNA-214 (miR-214) as the contributing factor for CRC. Mitochondrial transcription factor A (TFAM) and miR-214 expression in tumor samples from colorectal cancer patients and cancer cell lines were examined by reverse transcription and real-Time PCR (qPCR) or Western Blotting. Results: Our data demonstrated that miR-214 was significantly down-regulated in the tissue samples from CRC patients as well as CRC derived cell lines. TFAM overexpression was also observed in CRC patients and identified as a target for miR-214. Knockdown of TFAM by miR-214 mimics significantly inhibited the proliferation of CRC cell lines. Also, down-regulation of TFAM inhibited nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear translocation and the expression of NF-κB depended genes. Conclusion: In conclusion, our data suggested that down-regulation of MiR-214 contributed to the enhanced TFAM expression and decreased proliferation of CRC cells.

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“…The tumour suppressor p53 plays an important role in many cellular processes, such as apoptosis, DNA repair, cell cycle arrest, angiogenesis or mitochondrial quality check . Mutations in the TP53 gene are frequently observed in CC cells, and most of them result in the loss of normal protein function .…”

Section: Discussionmentioning

confidence: 99%

“…p53 is a transcription factor that can regulate the expression of genes participating in mitochondrial quality control checks. For example, genes encoding TFAM or spermatogenesis associated 18 protein (SPATA18) were found to be the transcriptional targets for p53. Although TFAM functions as a mitochondrial transcription factor, which also plays an important role in mtDNA replication and repair, the SPATA18 mediates the repair or elimination of dysfunctional mitochondria in response to mitochondrial damage .…”

Section: Introductionmentioning

confidence: 99%

TP53 somatic mutations are associated with somatic mitogenome substitutions but not indels in colorectal cancer cells

Skonieczna

Jawień

Marszałek

et al. 2019

The Journal of Gene Medicine

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Background p53 is a tumour suppressor protein that is involved in many cancer‐related processes. Growing evidence suggests that p53 also plays an important role in mitochondrial (mtDNA) maintenance. Somatic mitogenome mutations are frequently observed in colorectal cancer (CC) cells. Thus, it was important to determine whether somatic mtDNA changes are associated with TP53 mutational status. Methods In the present study, we analysed the TP53 gene in 67 CC patients, for whom mitogenome haplotypes were previously described. In total, 134 TP53 sequences (of cancer and matched normal specimens) were determined using the dideoxy method. Results Nine hereditary polymorphisms in the TP53 gene were detected in normal colon cells. None of them (neither alleles, nor genotypes) was associated with somatic mitogenome mutations in CC cells. Moreover, 42 somatic TP53 mutations were found in approximately 36% of CC tissues. These somatic changes were significantly more frequent in CC cells with somatic mtDNA mutations (p = 0.0069). Furthermore, we show that only mitochondrial somatic substitutions (p = 0.0017), but not indels (p > 0.05), were associated with somatic TP53 mutations. Conclusions The results of the present study suggest that changes in TP53 may modify p53 properties, which may result in the accumulation of somatic substitutions in CC mitogenomes.

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p53 increase mitochondrial copy number via up-regulation of mitochondrial transcription factor A in colorectal cancer

Cited by 31 publications

References 35 publications

Down‐regulation of TFAM increases the sensitivity of tumour cells to radiation via p53/TIGAR signalling pathway

Down‐regulation of TFAM increases the sensitivity of tumour cells to radiation via p53/TIGAR signalling pathway

Down-Regulation of MicroRNA-214 Contributed to the Enhanced Mitochondrial Transcription Factor A and Inhibited Proliferation of Colorectal Cancer Cells

TP53 somatic mutations are associated with somatic mitogenome substitutions but not indels in colorectal cancer cells

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