GATA4 inhibits expression of the tryptophan oxygenase gene by binding to the TATA box in fetal hepatocytes

Kaneoka, Hidenori; Miyake, Katsuhide; Iijima, Shinji

doi:10.1007/s10616-007-9120-1

Cited by 2 publications

(3 citation statements)

References 13 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, these sites are not conserved between human and rodents, suggesting that GATA4 may not directly bind to the regulatory sequences of ATG genes to repress their expression. Interestingly, GATA4 has been shown to inhibit the expression of tryptophan oxygenase gene in fetal hepatocytes by directly binding to the TATA box and interfering with the formation of the transcription initiation complex (59). It is, thus, possible that GATA4 may repress ATG genes through a similar mechanism without the need to bind to a GATA motif.…”

Section: Discussionmentioning

confidence: 99%

Transcription Factor GATA4 Inhibits Doxorubicin-induced Autophagy and Cardiomyocyte Death

Kobayashi¹,

Volden

Timm

et al. 2010

Journal of Biological Chemistry

247

195

View full text Add to dashboard Cite

Doxorubicin (DOX) is a potent anti-tumor drug known to cause heart failure. The transcription factor GATA4 antagonizes DOX-induced cardiotoxicity. However, the protective mechanism remains obscure. Autophagy is the primary cellular pathway for lysosomal degradation of long-lived proteins and organelles, and its activation could be either protective or detrimental depending on specific pathophysiological conditions. Here we investigated the ability of GATA4 to inhibit autophagy as a potential mechanism underlying its protection against DOX toxicity in cultured neonatal rat cardiomyocytes. DOX markedly increased autophagic flux in cardiomyocytes as indicated by the difference in protein levels of LC3-II (microtubule-associated protein light chain 3 form 2) or numbers of autophagic vacuoles in the absence and presence of the lysosomal inhibitor bafilomycin A1. DOX-induced cardiomyocyte death determined by multiple assays was aggravated by a drug or genetic approach that activates autophagy, but it was attenuated by manipulations that inhibit autophagy, suggesting that autophagy contributes to DOX cardiotoxicity. DOX treatment depleted GATA4 protein levels, which predisposed cardiomyocytes to DOX toxicity. Indeed, GATA4 gene silencing triggered autophagy that rendered DOX more toxic, whereas GATA4 overexpression inhibited DOX-induced autophagy, reducing cardiomyocyte death. Mechanistically, GATA4 up-regulated gene expression of the survival factor Bcl2 and suppressed DOX-induced activation of autophagy-related genes, which may likely be responsible for the anti-apoptotic and anti-autophagic effects of GATA4. Together, these findings suggest that activation of autophagy mediates DOX cardiotoxicity, and preservation of GATA4 attenuates DOX cardiotoxicity by inhibiting autophagy through modulation of the expression of Bcl2 and autophagy-related genes. Doxorubicin (DOX)4 is a very effective anti-cancer drug with cardiotoxicity that culminates in congestive heart failure (1-3).The prevailing mechanism for DOX cardiotoxicity is oxidative stress that has been supported by the ability of several antioxidants to reduce DOX cardiotoxicity in animal studies (4 -8). Unfortunately, clinical trials have failed to reproduce these results in humans (9), suggesting that mechanisms other than oxidative stress might also contribute to DOX-induced heart failure (9 -13). In support of this notion, DOX has been shown to cause cardiac mitochondrial injury by both oxidative and non-oxidative mechanisms (14).Autophagy is the major cellular pathway for degrading and recycling long-lived proteins and organelles that are sequestered in double-membrane vesicles termed autophagosomes. After fusing with the lysosome to form autolysosome, the inner membrane and the contents are degraded and recycled. More than 30 autophagy-related (ATG) genes encode proteins essential for autophagy induction and the generation, maturation, and recycling of autophagosomes or autophagic vacuoles (15,16). Autophagy has long been recognized to provide a survival pathw...

show abstract

Section: Discussionmentioning

confidence: 99%

Transcription Factor GATA4 Inhibits Doxorubicin-induced Autophagy and Cardiomyocyte Death

Kobayashi¹,

Volden

Timm

et al. 2010

Journal of Biological Chemistry

247

195

View full text Add to dashboard Cite

show abstract

“…One potential mechanism is via ECR ␣-bound GATA4 sterically inhibiting transcription initiation complex formation at the TATA box. Steric hindrance has been observed for other GATA4-repressed targets, including the tryptophan oxygenase and COL1A2 promoters (18,52). This mechanism has also been suggested for the GATA4-dependent repression of autophagy-inducing gene expression in response to doxorubicin (21).…”

Section: Discussionmentioning

confidence: 88%

“…For semiquantitative reverse transcription (RT)-PCR, the reverse transcriptase PCR was carried out by using the SuperScript III first-strand synthesis system (Invitrogen, Carlsbad, CA). Briefly, 1 g of total RNA isolated with TRIzol reagent (Invitrogen) from NRVMs or mouse hearts was used for first-strand cDNA synthesis in a 20-l reaction mixture volume containing 500 ng of oligo(dT) [12][13][14][15][16][17][18] as the primer. Two microliters of the reverse transcription reaction mixture was then used for PCR amplification with a volume of 50 l containing primers specific for the ms1, Bcl2, or GAPDH gene.…”

Section: Methodsmentioning

confidence: 99%

Cardiac Expression of ms1/STARS, a Novel Gene Involved in Cardiac Development and Disease, Is Regulated by GATA4

Ounzain

Kobayashi

Peterson

et al. 2012

Molecular and Cellular Biology

View full text Add to dashboard Cite

g Ms1/STARS is a novel muscle-specific actin-binding protein that specifically modulates the myocardin-related transcription factor (MRTF)-serum response factor (SRF) regulatory axis within striated muscle. This ms1/STARS-dependent regulatory axis is of central importance within the cardiac gene regulatory network and has been implicated in cardiac development and postnatal cardiac function/homeostasis. The dysregulation of ms1/STARS is associated with and causative of pathological cardiac phenotypes, including cardiac hypertrophy and cardiomyopathy. In order to gain an understanding of the mechanisms governing ms1/ STARS expression in the heart, we have coupled a comparative genomic in silico analysis with reporter, gain-of-function, and loss-of-function approaches. Through this integrated analysis, we have identified three evolutionarily conserved regions (ECRs), ␣, SINA, and DINA, that act as cis-regulatory modules and confer differential cardiac cell-specific activity. Two of these ECRs, ␣ and DINA, displayed distinct regulatory sensitivity to the core cardiac transcription factor GATA4. Overall, our results demonstrate that within embryonic, neonatal, and adult hearts, GATA4 represses ms1/STARS expression with the pathologically associated depletion of GATA4 (type 1/type 2 diabetic models), resulting in ms1/STARS upregulation. This GATA4-dependent repression of ms1/STARS expression has major implications for MRTF-SRF signaling in the context of cardiac development and disease.

show abstract

GATA4 inhibits expression of the tryptophan oxygenase gene by binding to the TATA box in fetal hepatocytes

Cited by 2 publications

References 13 publications

Transcription Factor GATA4 Inhibits Doxorubicin-induced Autophagy and Cardiomyocyte Death

Transcription Factor GATA4 Inhibits Doxorubicin-induced Autophagy and Cardiomyocyte Death

Cardiac Expression of ms1/STARS, a Novel Gene Involved in Cardiac Development and Disease, Is Regulated by GATA4

Contact Info

Product

Resources

About