Analysis of ARD1 Function in Hypoxia Response Using Retroviral RNA Interference

Fisher, Tim S.; Etages, Shelley Des; Hayes, Lisa S.; Crimin, Kim; Li, Baiyong

doi:10.1074/jbc.m412055200

Cited by 86 publications

(79 citation statements)

References 32 publications

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“…However, the role of ARD1 in the regulation of HIF1a has been contradictory in that both the overexpression and silencing of ARD1 has no impact on the stability of HIF-1 or the mRNA levels of downstream target genes of HIF-1 (Bilton et al, 2005;Fisher et al, 2005). Recently, we showed that mARD1 225 -induced acetylation was repressed under hypoxia or in the presence of metastasis-associated protein 1 (Yoo et al, 2006), which strongly supports the role of ARD1 in the regulation of HIF-1a stability.…”

Section: -Mp Increases the Capillary-tube Formation Of Human Umbilicsupporting

confidence: 52%

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

et al. 2006

Oncogene

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Hypoxia-inducible factor-1a (HIF-1a) plays a central role in oxygen homeostasis. Previously, we reported that the orphan nuclear receptor Nur77 functions in stabilizing HIF-1a. Here, we demonstrate that 6-mercaptopurine (6-MP), an activator of the NR4A family members, enhances transcriptional activity of HIF-1. 6-MP enhanced the protein-level of HIF-1a as well as vascular endothelial growth factor (VEGF) in a dose-and timedependent manner. The induction of HIF-1a was abolished by the transfection of either a dominant-negative Nur77 mutant or si-Nur77, indicating a critical role of Nur77 in the 6-MP action. The HIF-1a protein level remained up to 60 min in the presence of 6-MP when de novo protein synthesis was blocked by cycloheximide, suggesting that 6-MP induces stabilization of the HIF-1a protein. The fact that 6-MP decreased the association of HIF-1a with von Hippel-Lindau protein and the acetylation of HIF-1a, may explain how 6-MP induced stability of HIF-1a. Further, 6-MP induced the transactivation function of HIF-1a by recruiting co-activator cyclic-AMP-responseelement-binding protein. Finally, 6-MP enhanced the expression of HIF-1a and VEGF, and the formation of capillary tubes in human umbilical vascular endothelial cells. Together, our results provide a new insight for 6-MP action in the stabilization of HIF-1a and imply a potential application of 6-MP in hypoxia-associated human vascular diseases.

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Section: -Mp Increases the Capillary-tube Formation Of Human Umbilicsupporting

confidence: 52%

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

et al. 2006

Oncogene

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“…GST, glutathione-S-transferase; HBx, HBV regulatory protein; HIF-1a, hypoxia-inducible factor-1a; ODD, oxygen-dependent degradation; WT, wild type. Jeong et al, 2002;Qian et al, 2006), the acetylation hypothesis remains controversial since human ARD1 does not, at least directly, acetylate HIF1a (Arnesen et al, 2005;Bilton et al, 2005Bilton et al, , 2006Fisher et al, 2005;Murray-Rust et al, 2006). Instead, diverse other mechanisms have been proposed for the HDAC inhibitor-induced HIF-1 regulation; Kong et al (2006) showed that HDAC inhibitors induced the proteasomal degradation of HIF-1a by interacting with HSP70 and thereby disrupted the HSP70/HSP90 axis function.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

et al. 2008

Oncogene

143

129

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Expression level of metastasis-associated protein 1 (MTA1) is closely related to tumor growth and metastasis in various cancers. Although increased expression level of MTA1 was observed in hepatocellular carcinoma (HCC), role of MTA1 complex containing histone deacetylase (HDAC) in hepatitis B virus (HBV)-associated hepatocarcinogenesis has not been studied. Here, we demonstrated that HBx strongly induced the expression of MTA1 and HDAC1 genes at transcription level. MTA1 and HDAC1/2 physically associated with hypoxia-inducible factor-1a (HIF-1a) in vivo in the presence of HBx, which was abolished by knockdown of MTA1 by short interfering RNA (siRNA). HBx induced deacetylation of the oxygen-dependent degradation domain of HIF-1a, which was accompanied with dissociation of prolyl hydroxylases and von Hippel-Lindau tumor suppressor from HIF-1a. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1a. Further, we observed that protein levels of MTA1 and HDAC1 were increased in the liver of HBxtransgenic mice. Also, there was a higher expression of HDAC1 in HCC than in the adjacent non-tumorous cirrhotic nodules in 10 out of 12 human HBV-associated HCC specimens. Together, our data indicate a positive cross talk between HBx and the MTA1/HDAC complex in stabilizing HIF-1a, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.

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“…However, its function in mammalian cells has not been defined. Recently, Fisher et al (12) showed that hARD1 knockdown is correlated with the down-regulation of proliferative genes and up-regulation of antiproliferative genes. Because the expressions of HIF-1-regulated genes were not found to be affected by the small interfering RNA (siRNA), hARD1 was suggested to be directly linked to cell proliferation, regardless of HIF-1.…”

Section: Introductionmentioning

confidence: 99%

Human Arrest Defective 1 Acetylates and Activates β-Catenin, Promoting Lung Cancer Cell Proliferation

Lim¹,

Park²,

2006

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Arrest defective 1 (ARD1), an acetyltransferase, is essential for the yeast life cycle. Although its human homologue (hARD1) has been identified, its biological functions in human cells remain unclear. In the present study, we examined the biological function of hARD1. In H1299 and A549 lung cancer cells, hARD1-silencing RNA inhibited cell proliferation and induced G 1 arrest. Cyclin D1 was also found to be downregulated in these growth-arrested cells, and the ectopic expression of cyclin D1 rescued cell growth. hARD1 knockdown repressed the promoter activity of the cyclin D1 gene, which inhibited the transcription of cyclin D1. Moreover, hARD1 knockdown reduced the binding of B-catenin/TCF4 transcription factor to cyclin D1 promoter and repressed its transcriptional activity. Inversely, hARD1 expression increased the transcriptional activity of B-catenin. Both endogenous and ectopically expressed hARD1 was coimmunoprecipitated with B-catenin. hARD1 knockdown did not affect B-catenin expression or degradation but noticeably reduced acetylated B-catenin. The B-catenin binding and acetylation by hARD1 were observed in vitro. Therefore, it is suggested that hARD1 participates in proliferation of lung cancer cells via the activation of

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Analysis of ARD1 Function in Hypoxia Response Using Retroviral RNA Interference

Cited by 86 publications

References 32 publications

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

Human Arrest Defective 1 Acetylates and Activates β-Catenin, Promoting Lung Cancer Cell Proliferation

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