The Histidine Triad Protein Hint1 Triggers Apoptosis Independent of Its Enzymatic Activity

Weiske, Jörg; Huber, Otmar

doi:10.1074/jbc.m513452200

Cited by 123 publications

(122 citation statements)

References 51 publications

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“…HINT1 binds and hydrolyses adenosine 5 0 -monophosphoramidate substrates. It is a ubiquitously expressed haploinsufficient tumor suppressor gene 16 that promotes apoptosis, 17 inhibits the transcriptional activity of beta-catenin/TCF4, USF2 and NFkappaB, and inhibits the expression of endogenous cyclin D1 and TGFbeta2. 18 How loss-of-function mutations in HINT1 can cause an axonal neuropathy is unknown.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

et al. 2013

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Distal hereditary motor neuropathies (dHMNs) are a heterogenous group of genetic disorders with length-dependent degeneration of motor axons. Obtaining a genetic diagnosis in patients with dHMN remains challenging. We performed exome sequencing in a diagnostic setting in 12 patients with a clinical diagnosis of dHMN. Potential disease-causing variants in genes associated with dHMN and other forms of inherited neuropathies/motor neuron diseases were validated using Sequenom. The coverage in the genes studied was 495% with an average coverage of 450 times. In none of the patients a mutations was found in genes previously reported to be associated with dHMN. However, in 2/12 patients a recessive mutation in histidine triad nucleotide binding protein 1 (HINT1, recently discovered as a cause of axonal neuropathy with neuromyotonia) was identified. Our results demonstrate the diagnostic value of exome sequencing for patients with inherited neuropathies. The phenotypic spectrum of recessive mutations in HINT1 includes dHMN. HINT1 should be added to the list of genes to check for in dHMN.

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Section: Discussionmentioning

confidence: 99%

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

et al. 2013

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“…Thereby, Hint1 reduces the ability of Pontin to activate reporter constructs or endogenous targets such as axin2 and cyclin D2. Hint1 is also required for the expression of p53 and its target bax, although it is not clear whether these effects also involve Pontin, Reptin and the Tip60 complex (63). However, the observation that Hint1 acts as a haplo-insufficient tumor suppressor (64,65) raises the possibility that it is an important modulator of the activity of the β-Catenin:Pontin axis.…”

Section: Transcriptional Repression By Reptin (And Pontin)mentioning

confidence: 91%

Control of transcription by Pontin and Reptin

Gallant¹

2007

Trends in Cell Biology

131

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Pontin and Reptin are two closely related members of the AAA+ family of DNA helicases. They have roles in diverse cellular processes, including the response to DNA double-strand breaks and the control of gene expression. The two proteins share residence in different multiprotein complexes, such as the Tip60, Ino80, SRCAP and Uri1 complexes in animals, which are involved (directly or indirectly) in transcriptional regulation, but they also function independently from each other. Both Reptin and Pontin repress certain transcriptional targets of Myc, but only Reptin is required for the repression of specific ?-catenin and nuclear factor-?B targets. Here, I review recent studies that have addressed the mechanisms of transcriptional control by Pontin and Reptin. 1Trends in Cell Biology 2007, 17(4): 187-192. Control of transcription by Pontin and ReptinPeter Gallant Zoologisches Institut, Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland; email: gallant@zool.unizh.ch; phone: +41446354812. AbstractPontin and Reptin are two closely related members of the AAA+ family of DNA helicases. They play roles in diverse cellular processes, including the response to DNA double-strand breaks and the control of gene expression. The two proteins share residence in different multi-protein complexes, such as the Tip60-, Ino80-, SRCAP-and Uri1-complexes in animals which are (directly or indirectly) involved in transcriptional regulation, but they also function independently from each other. Both Reptin and Pontin repress certain transcriptional targets of Myc, but only Reptin is required for the repression of specific β-Catenin and nuclear factor-κB targets. Here, I review recent studies that have addressed the mechanisms of transcriptional control by Pontin and Reptin.

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“…Hint1 is involved in the regulation of apoptotic pathways by inducing an upregulation of p53 expression coinciding with an upregulation of the proapoptotic factor Bax and a concomitant downregulation of the apoptosis inhibitor Bcl-2. Hint1 appears to modulate transcriptional regulation, cell cycle control, and induction of apoptosis [52].…”

Section: Functional Roles Of the Identified Proteinsmentioning

confidence: 99%

Exploring the biochemical mechanisms of cytotoxic gold compounds: a proteomic study

et al. 2010

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We have recently shown that a group of structurally diverse gold compounds are highly cytotoxic toward a panel of 36 human tumor cell lines through a variety of biochemical mechanisms. A classic proteomic approach is exploited here to gain deeper insight into those mechanisms. This investigation is focused on Auoxo6, a novel binuclear gold(III) complex, and auranofin, a clinically established gold(I) antiarthritic drug. First, the 72-h cytotoxicity profiles of Auoxo6 and auranofin were determined against A2780 human ovarian carcinoma cells. Subsequently, protein extraction from gold-treated A2780 cells sensitive to cisplatin and 2D gel electrophoresis separation were carried out according to established procedures. Notably, both metallodrugs caused relatively modest changes in protein expression in comparison with controls as only 11 out of approximately 1,300 monitored spots showed appreciable quantitative changes. Very remarkably, six altered proteins were in common between the two treatments. Eight altered proteins were identified by mass spectrometry; among them was ezrin, a protein associated with the cytoskeleton and involved in apoptosis. Interestingly, two altered proteins, i.e., peroxiredoxins 1 and 6, are known to play crucial roles in the cell redox metabolism. Increased cleavage of heterogeneous ribonucleoprotein H was also evidenced, consistent with caspase 3 activation. Overall, the results of the present proteomic study point out that the mode of action of Auoxo6 is strictly related to that of auranofin, that the induced changes in protein expression are limited and selective, that both gold compounds trigger caspase 3 activation and apoptosis, and that a few affected proteins are primarily involved in cell redox homeostasis.

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The Histidine Triad Protein Hint1 Triggers Apoptosis Independent of Its Enzymatic Activity

Cited by 123 publications

References 51 publications

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

Control of transcription by Pontin and Reptin

Exploring the biochemical mechanisms of cytotoxic gold compounds: a proteomic study

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