Guardian of the Furnace: Mitochondria, TRAP1, ROS and stem cell maintenance

Kadye, Rose; Kramer, Adam H.; Joos-Vandewalle, Julia; Parsons, Michelle; Njengele, Zikhona; Hoppe, Heinrich C.; Prinsloo, Earl

doi:10.1002/iub.1234

Cited by 16 publications

(13 citation statements)

References 42 publications

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“…In addition, TRAP1-silenced colon carcinoma cells exhibited lack of clonogenic ability in vitro and tumor formation in mice xenografts [15], thus supporting the relevance of TRAP1 in early phases of colon carcinogenesis. It is also noteworthy that about 60% of human CRCs with high TRAP1 expression are characterized by the parallel upregulation of a network of proteins involved in several cell functions, critical for colon carcinogenesis [5, 10, 11, 13, 14, 18, 27, 28]. Thus, it is intriguing to speculate that TRAP1 upregulation may represent an early mechanism used by colon cancer cells to adapt to unfavorable environmental conditions and, thus, activate a number of pathways responsible for malignant transformation and tumor progression.…”

Section: Discussionmentioning

confidence: 99%

TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma

et al. 2017

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TRAP1 is a HSP90 molecular chaperone upregulated in colorectal carcinomas and involved in control of intracellular signaling, cell cycle, apoptosis and drug resistance, stemness and bioenergetics through co-traslational regulation of a network of client proteins. Thus, the clinical significance of TRAP1 protein network was analyzed in human colorectal cancers. TRAP1 and/or its client proteins were quantified, by immunoblot analysis, in 60 surgical specimens of colorectal carcinomas at different stages and, by immunohistochemistry, in 9 colorectal adenomatous polyps, 11 in situ carcinomas and 55 metastatic colorectal tumors. TRAP1 is upregulated at the transition between low-and high-grade adenomas, in in situ carcinomas and in about 60% of human colorectal carcinomas, being downregulated only in a small cohort of tumors. The analysis of TCGA database showed that a subgroup of colorectal tumors is characterized by gain/loss of TRAP1 copy number, this correlating with its mRNA and protein expression. Interestingly, TRAP1 is co-expressed with the majority of its client proteins and hierarchical cluster analysis showed that the upregulation of TRAP1 and associated 6-protein signature (i.e., IF2α, eF1A, TBP7, MAD2, CDK1 and βCatenin) identifies a cohort of metastatic colorectal carcinomas with a significantly shorter overall survival (HR 5.4; 95% C.I. 1.1-26.6; p=0.037). Consistently, the prognostic relevance of TRAP1 was confirmed in a cohort of 55 metastatic colorectal tumors. Finally, TRAP1 positive expression and its prognostic value are more evident in left colon cancers. These data suggest that TRAP1 protein network may provide a prognostic signature in human metastatic colorectal carcinomas.

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Section: Discussionmentioning

confidence: 99%

TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma

et al. 2017

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“…This gene encodes tumor necrosis factor receptor-associated protein 1, a mitochondrial chaperone involved in antioxidant defense [1, 2, 3]. Sequence variants in the C-terminal domain of this gene have recently been associated with congenital malformations and Leigh syndrome [4, 5].…”

Section: Introductionmentioning

confidence: 99%

Hurt, tired and queasy: Specific variants in the ATPase domain of the TRAP1 mitochondrial chaperone are associated with common, chronic “functional” symptomatology including pain, fatigue and gastrointestinal dysmotility

et al. 2015

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Functional disorders are common conditions with a substantial impact on a patients’ wellbeing, and can be diagnostically elusive. There are bidirectional associations between functional disorders and mitochondrial dysfunction. In this study, provided clinical information and the exon sequence of the TRAP1 mitochondrial chaperone were retrospectively reviewed with a focus on the functional categories of chronic pain, fatigue and gastrointestinal dysmotility. Very-highly conserved TRAP1 variants were identified in 73 of 930 unrelated patients. Functional symptomatology is strongly associated with specific variants in the ATPase binding pocket. In particular, the combined presence of all three functional categories is strongly associated with p.Ile253Val (OR 7.5, P=0.0001) and with two other interacting variants (OR 18, P=0.0005). Considering a 1–2% combined variant prevalence and high odds ratios, these variants may be an important factor in the etiology of functional symptomatology.

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“…TRAP1 has received extensive attention in the fields of tumor cell proliferation, differentiation, apoptosis, and survival (10,13). Targeted regulation of TRAP1 is currently of great interest in tumor therapy (14,15).…”

Section: Discussionmentioning

confidence: 99%

TRAP1 ameliorates renal tubulointerstitial fibrosis in mice with unilateral ureteral obstruction by protecting renal tubular epithelial cell mitochondria

Chen

Xie

et al. 2017

FASEB j.

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Mitochondrial dysfunction causes renal tubular epithelial cell injury and promotes cell apoptosis and renal tubulointerstitial fibrosis (TIF) progression. TNF receptor-associated protein 1 (TRAP1) is a molecular chaperone protein that is localized in mitochondria. It plays an important role in cell apoptosis; however, its functional mechanism in TIF remains unclear. In this study, we observed the effects of TRAP1 in renal tubular epithelial cell mitochondria in mice with unilateral ureteral obstruction and its function in cell apoptosis and TIF. Results show that TRAP1 could protect the mitochondrial structure in renal tubular epithelial cells; maintain the levels of mitochondrial membrane potential, ATP, and mitochondrial DNA copy number; inhibit reactive oxygen species production; stabilize the expression of the mitochondrial inner membrane protein mitofilin; reduce renal tubular epithelial cell apoptosis; and inhibit TIF. These results provide new theoretical foundations for additional understanding of the antifibrotic mechanism of TRAP1 in the kidney.-Chen, J.-F., Wu, Q.-S., Xie, Y.-X., Si, B.-L., Yang, P.-P., Wang, W.-Y., Hua, Q., He, Q. TRAP1 ameliorates renal tubulointerstitial fibrosis in mice with unilateral ureteral obstruction by protecting renal tubular epithelial cell mitochondria.

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Guardian of the Furnace: Mitochondria, TRAP1, ROS and stem cell maintenance

Cited by 16 publications

References 42 publications

TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma

TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma

Hurt, tired and queasy: Specific variants in the ATPase domain of the TRAP1 mitochondrial chaperone are associated with common, chronic “functional” symptomatology including pain, fatigue and gastrointestinal dysmotility

TRAP1 ameliorates renal tubulointerstitial fibrosis in mice with unilateral ureteral obstruction by protecting renal tubular epithelial cell mitochondria

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