Involvement of GADD153 and Cardiac Ankyrin Repeat Protein in Hypoxia-induced Apoptosis of H9c2 Cells

Han, Xue-Ji; Chae, Jei-Keon; Lee, Mi-Jin; You, Kyung-Ran; Lee, Byung-Ho; Kim, Dae‐Ghon

doi:10.1074/jbc.m501095200

Cited by 44 publications

(48 citation statements)

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“…Expression of several ankyrin repeat proteins was found to be associated with cell survival (Miles et al, 2005). In this regard, forced expression of normally sized ankrd1 in rat embryonic cardiomyocytes (Han et al, 2005) and human microvascular endothelial cells (Samaras et al, 2007) increases their resistance to Dox-induced stress/apoptosis which correlates with a decrease in caspase-3 activity. It is not clear whether intron-retaining ankrd1 variants, up-regulated in myocardium of piglets exposed to Dox, have a similar functional phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Although the functions of ankrd1 in the myocardium are still poorly delineated, several recent reports emphasize the role of ankrd1 in the protection of cardiac (Han et al, 2005) and microvascular endothelial (Samaras et al, 2007) cells against apoptosis and this gene's involvement in the adaptive response of ventricular myocardium to pressure overload . In addition, ankrd1 has also been identified as a candidate gene that can play an important role in congenital cardiac (Cinquetti et al, 2008) and skeletal muscle (Bakay et al, 2002;Nakada et al, 2003) disease, as well as in angiogenesis (Boengler et al, 2003), neovascularization (Shi et al, 2005;Samaras et al, 2007) and neurite outgrowth (Stam et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Intron retention generates ANKRD1 splice variants that are co-regulated with the main transcript in normal and failing myocardium

Torrado

Iglesias

Nespereira

et al. 2009

Gene

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The cardiac ankyrin repeat domain 1 protein (ANKRD1, also known as CARP) has been extensively characterized with regard to its proposed functions as a cardio-enriched transcriptional co-factor and stressinducible myofibrillar protein. The present results show the occurrence of alternative splicing by intron retention events in the pig and human ankrd1 gene. In pig heart, ankrd1 is expressed as four alternatively spliced transcripts, three of which have non-excised introns: ankrd1-contained introns 6, 7 and 8 (i.e., ankrd1-i6,7,8), ankrd1-contained introns 7 and 8 (i.e., ankrd1-i7,8), and ankrd1 retained only intron 8 (i.e., ankrd1-i8). In the human heart, two orthologues of porcine intron-retaining ankrd1 variants (i.e., ankrd1-i8 and ankrd1-i7,8) are detected. We demonstrate that these newly-identified intron-retaining ankrd1 transcripts are functionally intact, efficiently translated into protein in vitro and exported to the cytoplasm in cardiomyocytes in vivo. In the piglet heart, both the intronless and intron-retaining ankrd1 mRNAs are co-expressed in a chamber-dependent manner being more abundant in the left as compared to the right myocardium. Our data further indicate co-upregulation of the ankrd1 spliced variants in myocardium in the porcine model of diastolic heart failure. Most significantly, we demonstrate that in vivo forced expression of recombinant intronless ankrd1 markedly increases the levels of intron-retaining ankrd1 variants (but not of the endogenous main transcript) in piglet myocardium, suggesting that ANKRD1 may positively regulate the expression of its own intron-containing RNAs in response to cardiac stress. Overall, our findings demonstrate that in cardiomyocytes ANKRD1 can exist in multiple isoforms which may contribute to the functional diversity of this factor in heart development and disease. Abbreviations ANKRD1, ankyrin repeat domain 1 protein; MARPs, muscle ankyrin repeat proteins; SRF, serum response factor; HF, heart failure; DHF, diastolic HF; LV/RV, left/right ventricular myocardium; LA/RA, left/right atrial

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intron retention generates ANKRD1 splice variants that are co-regulated with the main transcript in normal and failing myocardium

Torrado

Iglesias

Nespereira

et al. 2009

Gene

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“…Overexpression of DDIT3 sensitized these cells to hypoxia-induced apoptosis, whereas antisense GADD153 had the opposite effect. 21 Like ANXA1, DDIT3 has at least one p53 binding site ( Table 1).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induces p53-dependent transactivation and Fas/CD95-dependent apoptosis

et al. 2006

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p53 triggers apoptosis in response to cellular stress. We analyzed p53-dependent gene and protein expression in response to hypoxia using wild-type p53-carrying or p53 null HCT116 colon carcinoma cells. Hypoxia induced p53 protein levels and p53-dependent apoptosis in these cells. cDNA microarray analysis revealed that only a limited number of genes were regulated by p53 upon hypoxia. Most classical p53 target genes were not upregulated. However, we found that Fas/CD95 was significantly induced in response to hypoxia in a p53-dependent manner, along with several novel p53 target genes including ANXA1, DDIT3/ GADD153 (CHOP), SEL1L and SMURF1. Disruption of Fas/CD95 signalling using anti-Fas-blocking antibody or a caspase 8 inhibitor abrogated p53-induced apoptosis in response to hypoxia. We conclude that hypoxia triggers a p53-dependent gene expression pattern distinct from that induced by other stress agents and that Fas/CD95 is a critical regulator of p53-dependent apoptosis upon hypoxia. The tumor suppressor p53 regulates cellular processes such as cell cycle progression, DNA repair and apoptosis. 1 p53 is stabilized and activated in response to different types of cellular stress, for example, DNA damage, oncogenic signalling and hypoxia, and induces a biological response through transcriptional regulation of downstream target genes. The molecular mechanisms that dictate the decision of a cell to enter growth arrest or undergo apoptosis or both in response to p53 activation are only partially understood. Also, it remains unclear why different cell types display differential response to functional p53. The biological outcome of p53 activation presumably depends on several factors, including cellular context, cell type and type of stress agent. 1 It is plausible that p53 activates different specific and possibly overlapping set of target genes in response to different stress signals. Therefore, knowledge about the target genes and their regulation under different conditions is vital for the understanding of p53-mediated tumor suppression.Previous DNA microarray studies have allowed a global analysis of p53-dependent gene expression in response to p53 activation by various means. 2,3 These studies have indicated that several hundred genes are potentially regulated by p53. Moreover, in silico analysis of the human genome sequence has revealed that up to 4800 genes contain one or more potential p53 binding sites. 4,5 Thus, it is conceivable that a large number of genes are regulated by p53, although not necessarily in the same cell in response to the same stress signal. Microarray studies have so far relied on artificial cell systems for activation of p53, for example, the metallothionein promoter or expression of exogenous p53. In addition, the numbers of genes on the arrays used have been relatively low. Thus, further studies of p53-dependent gene expression based on activation of endogenous p53 in response to physiological cellular stress should provide more reliable information about p53-dependent stress respon...

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“…Cdkn1a (p21), an important mediator of p53-dependent cell cycle arrest has also been reported to be up-regulated during hypoxia through the action of Hif-1 (BossenmeyerPourie et al 2002;Goda et al 2003). Both cdkn1a and Ddit3, which mediate ER-stress pathways and hypoxiainduced apoptosis, have been reported to be specifically induced in models of TMT intoxication (Jenkins and Barone 2004;Ogita et al 2004;Tajiri et al 2004;Han et al 2005;Lefebvre d'Hellencourt and Harry 2005).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐like transcriptional activation in TMT‐induced degeneration: microarray expression analysis on PC12 cells

Lattanzi¹,

Bernardini²,

Gangitano³

et al. 2006

Journal of Neurochemistry

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To more clearly elucidate the complete network of molecular mechanisms induced by trimethyltin (TMT) toxicity, we used a homogeneous cell culture model represented by PC12 cells treated with 1 and 5 lmol/L TMT for 24 h. The gene expression profile was performed by microarray analysis, enabling us to identify 189 genes that were significantly modulated in treated cells, compared with controls. The main effects of TMT on gene expression seem to be related to the activation of metabolic processes (glycolysis and lipogenesis) along with cell death pathways, membrane remodeling and intracellular biomolecules trafficking. These alterations are triggered by the neurotoxicant earlier than a strong decrease in cell viability, which occurs at higher TMT concentrations or at later time points. Some aspects of the transcriptional modulation observed in this study resemble the gene activation known to occur during cell response to hypoxia. Other cell toxicants have also been reported to exert similar effects on gene expression. Therefore, our data help to delineate general basic adaptive mechanisms possibly shared by cells responding to different death-inducing noxae, such as TMT.

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Involvement of GADD153 and Cardiac Ankyrin Repeat Protein in Hypoxia-induced Apoptosis of H9c2 Cells

Cited by 44 publications

References 42 publications

Intron retention generates ANKRD1 splice variants that are co-regulated with the main transcript in normal and failing myocardium

Intron retention generates ANKRD1 splice variants that are co-regulated with the main transcript in normal and failing myocardium

Hypoxia induces p53-dependent transactivation and Fas/CD95-dependent apoptosis

Hypoxia‐like transcriptional activation in TMT‐induced degeneration: microarray expression analysis on PC12 cells

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