DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein

Tran, Hien G.; Brunet, Anne; Grenier, Jill M.; Datta, Sandeep Robert; Fornace, Albert J.; DiStefano, Peter S.; Chiang, Laura; Greenberg, Michael E.

doi:10.1126/science.1068712

Cited by 770 publications

(633 citation statements)

References 19 publications

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“…Therefore, the difference of Gadd45a expression in MEFs isolated from E14.5 embryos is discernible, but becomes obvious in tissues from 6-month-old WT and TR4KO mice. It has been shown that FOXO3a can directly up-regulate the expression of Gadd45a during genotoxic stress [24]. Here, we find that IR poorly induces Gadd45a expression in TR4KO cells and TR4 can directly regulate transcription of Gadd45a .…”

Section: Discussionsupporting

confidence: 57%

“…By using DNA Damage Signaling Pathway focused PCR Array (SABiosciences ™ ), we found that expression of several genes controlling cell cycle arrest, including Gadd45a (growth arrest and DNA-damage-inducible, alpha), was reduced in TR4 knockdown cells (data not shown). Gadd45a is reported to be induced by multiple types of genotoxic stress including ultraviolet radiation and ionizing radiation (IR) [22, 23], and is downstream of the FOXO3a stimulated DNA repair pathway when cells are exposed to genotoxic stress [24]. We therefore suggest that TR4 is the mediator through which FOXO3a regulates GADD45A to promote DNA repair and protect cells from IR-induced cell death.…”

Section: Introductionmentioning

confidence: 99%

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Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation

Yan

Lee

Ting

et al. 2012

Cellular and Molecular Biology Letters

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The testicular receptor 4 (TR4) is a member of the nuclear receptor superfamily that controls various biological activities. A protective role of TR4 against oxidative stress has recently been discovered. We here examined the protective role of TR4 against ionizing radiation (IR) and found that small hairpin RNA mediated TR4 knockdown cells were highly sensitive to IR-induced cell death. IR exposure increased the expression of TR4 in scramble control small hairpin RNA expressing cells but not in TR4 knockdown cells. Examination of IR-responsive molecules found that the expression of Gadd45a, the growth arrest and DNA damage response gene, was dramatically decreased in Tr4 deficient (TR4KO) mice tissues and could not respond to IR stimulation in TR4KO mouse embryonic fibroblast cells. This TR4 regulation of GADD45A was at the transcriptional level. Promoter analysis identified four potential TR4 response elements located in intron 3 and exon 4 of the GADD45A gene. Reporter and chromatin immunoprecipitation (ChIP) assays provided evidence indicating that TR4 regulated the GADD45A expression through TR4 response elements located in intron 3 of the GADD45A gene. Together, we find that TR4 is essential in protecting cells from IR stress. Upon IR challenges, TR4 expression is increased, thereafter inducing GADD45A through transcriptional regulation. As GADD45A is directly involved in the DNA repair pathway, this suggests that TR4 senses genotoxic stress and up-regulates GADD45A expression to protect cells from IR-induced genotoxicity.

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Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation

Yan

Lee

Ting

et al. 2012

Cellular and Molecular Biology Letters

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“…Conversely, ectopic overexpression of tamoxifen‐inducible forms of FOXO1 (FOXO1‐ER) or FOXO3 (FOXO3‐ER) in human immortalized NP cells (Sakai et al, 2004) increased mRNA levels of SESN3 , MAP1LC3 , GABARAPL1 , and PRKAA2 (Figure 5f). This transcriptional activation of homeostatic genes was likely a direct function of FOXO as overexpression of a FOXO3 mutant that lacks the DNA binding region (FOXO3‐∆DBD‐ER) (Tran et al, 2002) did not change gene expression (Supporting information Figure S8 in Appendix S1). In addition, LC3‐II levels were significantly elevated in cells overexpressing FOXO1 or FOXO3 (Figure 5g), indicating that FOXO is sufficient to stimulate autophagy in NP cells.…”

Section: Resultsmentioning

confidence: 99%

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

et al. 2018

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Intervertebral disk (IVD) degeneration is a prevalent age‐associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age‐related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO‐deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.

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“…Members of the MyD/Gadd (growth arrest and DNA damage response) gene family function to regulate transcription and cell proliferation (Zhan et al, 1994). Gadd45 is a DNA damage-responsive gene that occurs in three isoforms (a, b, and g) and functions in DNA repair, cell cycle checkpoint mechanisms, and apoptosis pathways (Kastan et al, 1992;Jin et al, 2000b;Sheikh et al, 2000;Tran et al, 2002). Several studies suggest that BRCA1 up-regulates the expression of Gadd45 (¼ Gadd45a), in part, by activating the Gadd45 promoter (Harkin et al, 1999;Jin et al, 2000a).…”

Section: Regulation Of Transcriptionmentioning

confidence: 99%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

237

195

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The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast cancer and breast-ovarian cancer syndromes in women. While inherited mutations of BRCA1 are responsible for about 40-45% of hereditary breast cancers, these mutations account for only 2-3% of all breast cancers, since the BRCA1 gene is rarely mutated in sporadic breast cancers. However, BRCA1 expression is frequently reduced or absent in sporadic cancers, suggesting a much wider role in mammary carcinogenesis. Since BRCA1 was cloned in 1994, its molecular function has been the subject of intense investigation. These studies have revealed multiple functions of the BRCA1 that may contribute to its tumor suppressor activity, including roles in: cell cycle progression, several highly specialized DNA repair processes, DNA damage-responsive cell cycle checkpoints, regulation of a set of specific transcriptional pathways, and apoptosis. Many of these functions are linked to protein:protein interactions involving different portions of the 1,863 amino acid (aa) BRCA1 protein. BRCA1 functions in cell cycle progression and the DNA damage response appear to be regulated by distinct and specific phosphorylation events, but the molecular pathways activated by these phosphorylations are only beginning to be unraveled. In addition, the reason that BRCA1 mutation carriers develop specific tumor types (breast and ovarian cancers in women and possibly prostate cancers in men) is not clearly understood. Elucidation of the precise molecular functions of the BRCA1 gene product will greatly enhance our understanding of the pathogenesis of hereditary as well as sporadic mammary carcinogenesis.

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DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein

Cited by 770 publications

References 19 publications

Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation

Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

BRCA1 gene in breast cancer

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