HAX-1, Identified by Differential Display Reverse Transcription Polymerase Chain Reaction, Is Overexpressed in Lesional Psoriasis

Mirmohammadsadegh, Alireza; Tartler, Ulrike; Michel, G; Baer, Annett; Walz, Markus; Wolf, Ronald; Ruzicka, Thomas; Hengge, Ulrich R.

doi:10.1046/j.1523-1747.2003.12247.x

Cited by 53 publications

(58 citation statements)

References 29 publications

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“…HAX-1 was originally isolated as an interactor of HS1 (10) to also interact with PKD2 (21), EBNA-LP (29,30), and K15-Kaposi's sarcoma proteins (22). Down-regulation of HAX-1 using antisense RNA has been shown to induce apoptosis in HaCaT cells (31). We found that HAX-1 protein could specifically interact with Omi in yeast; this interaction involved both the PDZ-domain and the catalytic domain of Omi.…”

Section: Discussionmentioning

confidence: 88%

Regulation of HAX-1 Anti-apoptotic Protein by Omi/HtrA2 Protease during Cell Death

Cilenti

Soundarapandian

Kyriazis

et al. 2004

Journal of Biological Chemistry

166

144

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Omi/HtrA2 is a nuclear-encoded mitochondrial serine protease that has a pro-apoptotic function in mammalian cells. Upon induction of apoptosis, Omi translocates to the cytoplasm and participates in caspase-dependent apoptosis by binding and degrading inhibitor of apoptosis proteins. Omi can also initiate caspase-independent apoptosis in a process that relies entirely on its ability to function as an active protease. To investigate the mechanism of Omi-induced apoptosis, we set out to isolate novel substrates that are cleaved by this protease. We identified HS1-associated protein X-1 (HAX-1), a mitochondrial anti-apoptotic protein, as a specific Omi interactor that is cleaved by Omi both in vitro and in vivo. HAX-1 degradation follows Omi activation in cells treated with various apoptotic stimuli. Using a specific inhibitor of Omi, HAX-1 degradation is prevented and cell death is reduced. Cleavage of HAX-1 was not observed in a cell line derived from motor neuron degeneration 2 mice that carry a mutated form of Omi that affects its proteolytic activity. Degradation of HAX-1 is an early event in the apoptotic process and occurs while Omi is still confined in the mitochondria. Our results suggest that Omi has a unique pro-apoptotic function in mitochondria that involves removal of the HAX-1 antiapoptotic protein. This function is distinct from its ability to activate caspase-dependent apoptosis in the cytoplasm by degrading inhibitor of apoptosis proteins.Omi/HtrA2 is a mitochondrial serine protease that is released to the cytoplasm upon induction of apoptosis (1-4). In the cytoplasm, Omi binds and cleaves IAPs 1 leading to activation of caspase-dependent apoptosis (5, 6). Omi can also induce caspase-independent apoptosis through an as yet unknown mechanism that requires its proteolytic activity (7,8). In addition to its pro-apoptotic function, Omi has another unique role in maintaining mitochondrial homeostasis, but the details of this mechanism are still unclear (9). The serine protease activity of Omi is necessary and essential for its normal function whether it acts as a pro-apoptotic protein in the cytoplasm or as a potential chaperone in the mitochondria (9). The proteolytic activity of Omi has been associated with autoprocessing to form the mature protein as well as cleavage of IAPs to activate caspase-dependent apoptosis (5,6,8). To understand the mechanism of Omi's function, it will be necessary to identify new substrates for this protease. These substrates might be mitochondrial or cytoplasmic proteins, and their degradation and removal by Omi could be part of the apoptotic process. In this report, we used the yeast two-hybrid system to isolate and characterize new Omi-interacting proteins. One of these interactors isolated from this screen was the HS1-associated protein X-1 (HAX-1) anti-apoptotic protein (10). HAX-1 interacted with Omi both in vitro and in vivo. Furthermore, HAX-1 was degraded and removed by Omi when cells were treated with various apoptotic stimuli. Using a specific inhibitor of the pro...

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Section: Discussionmentioning

confidence: 88%

Regulation of HAX-1 Anti-apoptotic Protein by Omi/HtrA2 Protease during Cell Death

Cilenti

Soundarapandian

Kyriazis

et al. 2004

Journal of Biological Chemistry

166

144

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“…Furthermore, it has been demonstrated that HAX1 is degraded in the mitochondria by the high temperature requirement protein A2 (Omi/HtrA2) after induction of apoptosis, which contributes to caspase-independent induction of apoptosis by Omi/HtrA2 (17). An additional study showed both that HAX1 is overexpressed in psoriatic skin using in situ hybridization and that keratinocytes isolated from psoriatic plaques, which are characterized by hyperproliferation and resistance to apoptosis, also overexpressed HAX1 (18). Recently, it was reported that HAX1 is an anti-apoptotic molecule that protects cardiac myocytes from hypoxia/reoxygenation-induced apoptosis by inhibiting caspase-9 (19,20).…”

Section: Introductionmentioning

confidence: 99%

hSav1 interacts with HAX1 and attenuates its anti-apoptotic effects in MCF-7 breast cancer cells

Luo

Li²,

Li³

et al. 2011

Int J Mol Med

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Abstract. It has been reported that Salvador (SAV) is a core component of the Salvador-Warts-Hippo (SWH) pathway that restricts cell number, by functioning as a dual regulator of cell proliferation and apoptosis in Drosophila. However, the function of its human ortholog hSav1 (also called hWW45) in mammalian cells is poorly understood. In this study, we identified hematopoietic cell-specific protein 1 (HS1)-associated protein X-1 (HAX1), a 35-kda protein localized to cell mitochondria, as a novel binding partner of hSav1 using a yeast two-hybrid screening technique. Our finding was confirmed by immunoprecipitation and glutathione-S-transferase (GST) pull-down assays of both proteins. Using immunofluorescence staining, we showed that HAX1 and hSav1 interact with each other. Analysis of the anti-apoptotic function of HAX1 revealed that the presence of hSav1 attenuated the HAX1 protective effects from hydrogen peroxide (H 2 O 2 )-induced cell death in McF-7 cells, while knockdown of hSav1 by small interfering RNAs (siRNAs) significantly enhanced the anti-apoptotic function of HAX1. Also, using the Oncomine database, we found several studies in which HAX1 levels were significantly up-regulated and hSav1 expression was down-regulated in breast cancer samples compared to normal breast tissue. In summary, we conclude that hSav1 interacts with HAX1 and attenuates its protective role against apoptosis in McF-7 breast cancer cells.

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“…The biological function of HAX-1 was primarily divided into three categories: (i) association with viral proteins for involvement in apoptotic regulation processes, (ii) involvement in cell motility processes, and (iii) acting as a cytoplasmic retention factor. HAX-1 mRNA is expressed ubiquitously in different tissues, including liver (17,19). Several studies have shown that Hax-1 expression is upregulated in different types of tumors (7,14,17,41,42).…”

mentioning

confidence: 99%

Hepatitis C Virus Core Protein and Cellular Protein HAX-1 Promote 5-Fluorouracil-Mediated Hepatocyte Growth Inhibition

Banerjee¹,

Saito²,

Meyer³

et al. 2009

J Virol

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Hepatitis C virus (HCV) often causes chronic infection and may lead to hepatocellular carcinoma (HCC).We have shown previously that HCV core protein has pleiotropic functions, including transcriptional regulation of a number of cellular genes, although the mechanism for gene regulation remains unclear. In this study, a mammalian two-hybrid screen identified a novel binding partner, HS1-associated protein X-1 (HAX-1), for HCV core protein from a human liver cDNA library. An association between HAX-1 and HCV core protein was further verified by confocal microscopy and coimmunoprecipitation in HepG2 cells expressing HCV core or full-length (FL) gene. Both HCV core protein and a chemotherapeutic agent for HCC, 5-flouorouracil (5-FU), are known to modulate p53. We examined here whether an association between core and HAX-1 has any functional relevance to p53 modulation in 5-FU-treated cells. For this, the role of HAX-1 on 5-FU treatment was examined in HepG2 cells expressing HCV core or FL gene using cell proliferation, p53 expression, and caspase activation analysis. Cells expressing HCV-core or FL gene were more susceptible to 5-FU-induced growth inhibition than control cells, whereas cell survival was enhanced after suppression of HAX-1 by small interfering RNA. Further, 5-FU-mediated p53 expression was reduced with concurrent HAX-1 suppression in core-or polyprotein-expressing cells compared to control HepG2 cells, and caspase-2 and -7 activities were diminished. On the other hand, HCV core protein did not play a detectable role in 5-FU-mediated caspase-7 activation in the absence of functional p53 in Hep3B or Huh-7 cells. These observations underscore an association between HCV core and HAX-1, which promotes 5-FU mediated p53-dependent caspase-7 activation and hepatocyte growth inhibition.

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HAX-1, Identified by Differential Display Reverse Transcription Polymerase Chain Reaction, Is Overexpressed in Lesional Psoriasis

Cited by 53 publications

References 29 publications

Regulation of HAX-1 Anti-apoptotic Protein by Omi/HtrA2 Protease during Cell Death

Regulation of HAX-1 Anti-apoptotic Protein by Omi/HtrA2 Protease during Cell Death

hSav1 interacts with HAX1 and attenuates its anti-apoptotic effects in MCF-7 breast cancer cells

Hepatitis C Virus Core Protein and Cellular Protein HAX-1 Promote 5-Fluorouracil-Mediated Hepatocyte Growth Inhibition

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