Phospholamban Interacts with HAX-1, a Mitochondrial Protein with Anti-apoptotic Function

Vafiadaki, Elizabeth; Sanoudou, Despina; Arvanitis, Demetrios A.; Catino, Dawn H.; Kranias, Evangelia G.; Kontrogianni‐Konstantopoulos, Aikaterini

doi:10.1016/j.jmb.2006.10.057

Cited by 89 publications

(131 citation statements)

References 62 publications

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“…Upon interaction with other cellular proteins, its subcellular localization is redistributed, and this may play an important role in modulating different biological activities (19). Vafiadaki et al (38) reported that an association of HAX-1 with phospholamban, a key regulator of contractibility in the heart, leads to redistribution and colocalization of HAX-1 with phospholamban at the endoplasmic reticulum. This association enhances the protective effects of HAX-1 displayed against hypoxia/reoxygenation-induced cell death.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The membrane was washed four times in Tris-buffered saline-Tween 20, and reactive bands were detected using a Super Signal chemiluminescence substrate kit (Pierce). To ensure equal loading of samples in each lane, membranes were stripped and reprobed with a ␤-actin (total protein) or lamin (nuclear protein) antibody (24,51).…”

Section: Methodsmentioning

confidence: 99%

Elucidation of the signaling network of COX-2 induction in sheared chondrocytes: COX-2 is induced via a Rac/MEKK1/MKK7/JNK2/c-Jun-C/EBPβ-dependent pathway

Healy¹,

Zhu

Stull

et al. 2008

American Journal of Physiology-Cell Physiology

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Shear stress is a pathophysiologically relevant mechanical signal in cartilage biology and tissue engineering. Cyclooxygenase-2 (COX-2) is a pivotal proinflammatory enzyme, which is induced by mechanical loading-derived shear stress in chondrocytes. In the present study, we investigated the transcriptional machinery and signaling pathway regulating shear-induced COX-2 expression in human chondrocytic cells. Deletion and mutation analyses of the human cox-2 promoter reveal that the CCAAT/enhancer-binding protein (C/EBP) and activator protein-1 (AP-1) predominantly contribute to the shear-induced cox-2 promoter activity. Supershift assays disclose that C/EBPβ, but not C/EBPα or C/EBPδ, binds to the C/EBP site, whereas c-Jun binds to AP-1. Individual gene knockdown experiments demonstrate the direct regulation of C/EBPβ expression by c-Jun, and the critical roles of both c-Jun and C/EBPβ in shear-induced COX-2 synthesis. Our studies also indicate that Rac and, to a lesser extent, Cdc42 transactivate MEKK1, which is, in turn, responsible for activation of mitogen-activated protein kinase kinase 7 (MKK7). MKK7 regulates c-Jun NH2-terminal kinase 2 activation, which, in turn, triggers the phosphorylation of c-Jun that controls shear-mediated COX-2 upregulation in chondrocytes. Reconstructing the signaling network regulating shear-induced COX-2 expression and inflammation may provide insights to optimize conditions for culturing artificial cartilage in bioreactors and for developing therapeutic interventions for arthritic disorders.

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“…It was proposed that depending on the available interaction partners, the subcellular localization and functional properties of HAX-1 might vary among different tissues (Vafiadaki et al 2009b). Recently, PLN was identified via yeast two-hybrid screen and GST-pull-down experiments as a novel interaction partner of HAX-1 (Vafiadaki et al 2007). The site of the HAX-1 and PLN interaction is well documented and is confined to the regions 203-245 of HAX-1 and 16-22 of PLN, overlapping with the PLN phosphorylation sites (Vafiadaki et al 2007).…”

Section: Phospholamban and Sarcolipinmentioning

confidence: 99%

The Ca2+ Pumps of the Endoplasmic Reticulum and Golgi Apparatus

Vandecaetsbeek

Vangheluwe²,

Raeymaekers³

et al. 2011

Cold Spring Harbor Perspectives in Biology

185

170

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The various splice variants of the three SERCA-and the two SPCA-pump genes in higher vertebrates encode P-type ATPases of the P 2A group found respectively in the membranes of the endoplasmic reticulum and the secretory pathway. Of these, SERCA2b and SPCA1a represent the housekeeping isoforms. The SERCA2b form is characterized by a luminal carboxy terminus imposing a higher affinity for cytosolic Ca 2þ compared to the other SERCAs. This is mediated by intramembrane and luminal interactions of this extension with the pump. Other known affinity modulators like phospholamban and sarcolipin decrease the affinity for Ca 2þ . The number of proteins reported to interact with SERCA is rapidly growing. Here, we limit the discussion to those for which the interaction site with the ATPase is specified: HAX-1, calumenin, histidine-rich Ca 2þ -binding protein, and indirectly calreticulin, calnexin, and ERp57. The role of the phylogenetically older and structurally simpler SPCAs as transporters of Ca 2þ , but also of Mn 2þ , is also addressed.

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Phospholamban Interacts with HAX-1, a Mitochondrial Protein with Anti-apoptotic Function

Cited by 89 publications

References 62 publications

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

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

Elucidation of the signaling network of COX-2 induction in sheared chondrocytes: COX-2 is induced via a Rac/MEKK1/MKK7/JNK2/c-Jun-C/EBPβ-dependent pathway

The Ca2+ Pumps of the Endoplasmic Reticulum and Golgi Apparatus

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