FOXO3a Is Activated in Response to Hypoxic Stress and Inhibits HIF1-Induced Apoptosis via Regulation of CITED2

Bakker, Walbert J.; Harris, Isaac S.; Mak, Tak W.

doi:10.1016/j.molcel.2007.10.035

Cited by 238 publications

(210 citation statements)

References 58 publications

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“…Related to this observation, recent studies by Bakker et al indicated that by reducing expression of the proapoptotic genes NIX and RTP801 under hypoxic conditions, cited2 induced by HIF/FOXO3a signaling inhibited HIF-1-mediated apoptosis in fibroblasts and breast cancer cells (31). In cartilage, another hypoxic tissue, in response to shear forces and transforming growth factor ␤, cited2 down-regulates matrix metalloproteinase 1 (MMP-1) and MMP-13, enzymes that degrade the extracellular matrix and enhance the ability of chondrocytes to assume a terminally differentiated phenotype (32).…”

Section: Discussionmentioning

confidence: 88%

Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc

Agrawal¹,

Gajghate²,

Smith³

et al. 2008

Arthritis & Rheumatism

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Objective. To determine whether nucleus pulposus cells of the intervertebral disc express hypoxiainducible factor 2␣ (HIF-2␣), and to assess the role of HIF-1 and HIF-2 in controlling cited2 and vascular endothelial growth factor (VEGF) expression.Methods. Rat cells were cultured under normoxic (21% O 2 ) or hypoxic (2% O 2 ) conditions, and expression and promoter activity of HIF-2 target genes were evaluated. Gain-or loss-of-function experiments were performed to investigate the contribution of HIF isoforms to cited2 activity as well as the role of cited2 in regulating VEGF expression.Results. We found that HIF-2␣ protein was expressed in vivo and that protein and messenger RNA expression were similar under both normoxic and hypoxic conditions. However, there was a significant increase in HIF-2␣ transactivation under hypoxic conditions. With respect to functional activity, unlike the case in most other tissues, HIF-2 failed to increase the transcriptional activities of superoxide dismutase 2 and frataxin, 2 common target genes involved in radical dismutation. However, under hypoxic conditions, HIF-2 preferentially regulated the expression and promoter activity of cited2, a p300 binding protein. When HIF-2␣ or HIF-1␣ was suppressed, cited2 promoter activity was inhibited. Finally, we showed that forced expression or suppression of cited2 resulted in corresponding changes in expression of VEGF, a common target gene for HIF-1 and HIF-2 in the nucleus pulposus cells.Conclusion. Results of this study indicate that in nucleus pulposus cells, HIF-2 and HIF-1 modulate their own transcriptional activity through cited2. We suggest that the 2 arms of the regulatory circuit serve to maintain survival activities and inhibit angiogenesis in the healthy disc.

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Section: Discussionmentioning

confidence: 88%

Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc

Agrawal¹,

Gajghate²,

Smith³

et al. 2008

Arthritis & Rheumatism

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“…Its family member, CITED4, has been analysed in breast tumours and was found to be associated with HIF1a expression and to be either lost or translocated into the cytoplasm during tumour progression (Fox et al, 2004). CITED2 acts as a transcriptional co-factor and may regulate HIF1-stimulated apoptosis through FOXO3a (Bakker et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

CITED2 and NCOR2 in anti-oestrogen resistance and progression of breast cancer

et al. 2009

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BACKGROUND: Endocrine therapies of breast cancer are effective but ultimately fail because of the development of treatment resistance. We have previously revealed several genes leading to tamoxifen resistance in vitro by retroviral insertion mutagenesis. To understand the manner in which these genes yield tamoxifen resistance, their effects on global gene expression were studied and those genes resulting in a distinct gene expression profile were further investigated for their clinical relevance. METHODS: Gene expression profiles of 69 human breast cancer cell lines that were made tamoxifen resistant through retroviral insertion mutagenesis were obtained using oligonucleotide arrays and analysed with bioinformatic tools. mRNA levels of NCOR2 and CITED2 in oestrogen receptor-positive breast tumours were determined by quantitative RT -PCR. mRNA levels were evaluated for association with metastasis-free survival (MFS) in 620 patients with lymph node-negative primary breast cancer who did not receive systemic adjuvant therapy, and with clinical benefit in 296 patients receiving tamoxifen therapy for recurrent breast cancer. RESULTS: mRNA expression profiles of most tamoxifen-resistant cell lines were strikingly similar, except for the subgroups of cell lines in which NCOR2 or CITED2 were targeted by the retrovirus. Both NCOR2 and CITED2 mRNA levels were associated with MFS, that is, tumour aggressiveness, independently of traditional prognostic factors. In addition, high CITED2 mRNA levels were predictive for a clinical benefit from first-line tamoxifen treatment in patients with advanced disease. CONCLUSIONS: Most retrovirally targeted genes yielding tamoxifen resistance in our cell lines do not impose a distinctive expression profile, suggesting that their causative role in cell growth may be accomplished by post-transcriptional processes. The associations of NCOR2 and CITED2 with outcome in oestrogen receptor-positive breast cancer patients underscore the clinical relevance of functional genetic screens to better understand disease progression, which may ultimately lead to the development of improved treatment options.

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“…Lysine acetylation is a reversible process catalyzed by acetyltransferases and deacetylases (9). To identify the acetyltransferase responsible for TyrRS acetylation, we overexpressed p300/CBP-associated factor (PCAF), Tip60, and GCN5 into HEK293T cells, because PCAF, Tip60, and GCN5 have been shown to respond to oxidative stress (22)(23)(24)(25), and found that the acetylation of TyrRS was elevated only after the ectopic expression of PCAF, not the other acetyltransferases ( Fig. 2A).…”

Section: Significancementioning

confidence: 99%

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Cao

Xiao

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Tyrosyl-tRNA synthetase (TyrRS) is well known for its essential aminoacylation function in protein synthesis. Recently, TyrRS has been shown to translocate to the nucleus and protect against DNA damage due to oxidative stress. However, the mechanism of TyrRS nuclear localization has not yet been determined. Herein, we report that TyrRS becomes highly acetylated in response to oxidative stress, which promotes nuclear translocation. Moreover, p300/ CBP-associated factor (PCAF), an acetyltransferase, and sirtuin 1 (SIRT1), a NAD + -dependent deacetylase, regulate the nuclear localization of TyrRS in an acetylation-dependent manner. Oxidative stress increases the level of PCAF and decreases the level of SIRT1 and deacetylase activity, all of which promote the nuclear translocation of hyperacetylated TyrRS. Furthermore, TyrRS is primarily acetylated on the K244 residue near the nuclear localization signal (NLS), and acetylation inhibits the aminoacylation activity of TyrRS. Molecular dynamics simulations have shown that the in silico acetylation of K244 induces conformational changes in TyrRS near the NLS, which may promote the nuclear translocation of acetylated TyrRS. Herein, we show that the acetylated K244 residue of TyrRS protects against DNA damage in mammalian cells and zebrafish by activating DNA repair genes downstream of transcription factor E2F1. Our study reveals a previously unknown mechanism by which acetylation regulates an aminoacyl-tRNA synthetase, thus affecting the repair pathways for damaged DNA.

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FOXO3a Is Activated in Response to Hypoxic Stress and Inhibits HIF1-Induced Apoptosis via Regulation of CITED2

Cited by 238 publications

References 58 publications

Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc

Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc

CITED2 and NCOR2 in anti-oestrogen resistance and progression of breast cancer

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

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