SRC-3 Coactivator Functional Lifetime Is Regulated by a Phospho-Dependent Ubiquitin Time Clock

Wu, Ray-Chang; Feng, Qin; Lonard, David M.; O’Malley, Bert W.

doi:10.1016/j.cell.2007.04.039

Cited by 213 publications

(210 citation statements)

References 31 publications

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“…Results are consistent with numerous previous studies that demonstrate the phosphorylation of SRC-3 in response to estrogen, TNFa, epidermal growth factor, and RA (12,13,15,17,18,26,27). It has been shown that phosphorylation of SRC-3 affects the nuclear localization and interaction of the nuclear receptors with this coactivator as well as receptor-promoter interactions in response to various stimuli, thereby regulating cellular transcriptional activity (15,17,26). It has been proposed that phosphorylation of SRC-3 in response to RA initially promotes transcriptional activation with subsequent inhibition of RA-target genes as a result of SRC-3 degradation following prolonged RA exposure (13).…”

Section: Discussionsupporting

confidence: 81%

“…Data indicate that the decrease of SRC-3 induced by ATRA in neurons is p38 MAPK but not ERK MAPK dependent. It has been shown that selective SRC-3 phosphorylation regulates the turnover of this coactivator by ubiquination and proteasomal degradation (13,17). The decrease of SRC-3 in the cultured neuron cells occurred several hours later than the phosphorylation of SRC-3 observed in the current study, and this decrease was prevented by MG132, a specific proteasome inhibitor.…”

Section: Discussionmentioning

confidence: 43%

“…Many types of kinases are involved in the phosphorylation of SRC-3 in response to various stimuli. In response to estrogen or growth factors, SRC-3 is phosphorylated at different sites by PKA, and all three types of MAPK (p38, JNK, and ERK), IKK, and GSK3 (14)(15)(16)(17), as well as by aPKC (18). The phosphorylation and biological functions of SRC-3 could be cell type-, promoter-, and/or ligand-specific (15,18).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies in several types of cell lines have shown that SRC-3 is phosphorylated by different stimuli including steroid hormones, growth factors, tumor necrosis factor (TNF)a, and RA. The phosphorylation of SRC-3 involves various kinases such as p42/44 mitogen-activated protein kinase (MAPK) (14,15), c-Jun-N-terminal kinase (JNK), p38 MAPK (13,15,16), protein kinase A (PKA) (15), IjB kinase (IKKs) (15,16), glycogen synthase kinase (GSK)3 (15,17), and atypical protein kinase C (aPKC) (18). The phosphorylation of SRC-3 by different kinases and its subsequent functional changes could be cell type-and ligand-specific (15,18).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

p38 Mitogen‐activated protein kinase‐dependent regulation of SRC‐3 and involvement in retinoic acid receptor α signaling in embryonic cortical neurons

Chai

Yang

et al. 2009

IUBMB Life

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Appropriate retinoic acid (RA) signaling is essential in the development of the central nervous system (CNS). Previous studies have shown that RA activates p38 mitogen‐activated protein kinase (MAPK) and steroid receptor coactivator (SRC)‐3 in tumor cells in vitro. It is unknown whether the activation of p38 MAPK and SRC‐3 is involved in RA‐mediated CNS development. The current study investigated a possible role for p38 MAPK in the regulation of (SRC)‐3 phosphorylation/degradation and in retinoic acid receptor (RAR)α signaling in mouse fetal cortical neurons treated with all‐trans retinoic acid (ATRA). Results showed that ATRA treatment rapidly activated p38 MAPK, which in turn resulted in phosphorylation with subsequent degradation of SRC‐3. Inhibition of p38 MAPK by SB203580 blocked the phosphorylation and degradation of SRC‐3. The binding of RARα to retinoic acid responsive element (RARE) was rapidly increased in neurons following ATRA treatment. Inhibition of p38 MAPK significantly enhanced the RARα‐RARE binding activity, but had no effects on ATRA‐induced decrease of RARα. Treatment of the fetal cortical neurons with ATRA significantly increased the expression of HOXd3, a retinoid‐target gene. The increase of HOXd3 expression was augmented when p38 MAPK activity was inhibited by a specific inhibitor, SB203580. Results suggest that ATRA activates the p38 MAPK signal pathway with resultant degradation of SRC‐3, and that p38 MAPK is involved in the regulation of RARα‐mediated signaling in developing neurons. © 2009 IUBMB IUBMB Life, 61(6): 670–678, 2009

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 43%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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p38 Mitogen‐activated protein kinase‐dependent regulation of SRC‐3 and involvement in retinoic acid receptor α signaling in embryonic cortical neurons

Chai

Yang

et al. 2009

IUBMB Life

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“…Besides, the SRC family functions as coactivators not only for NR but also for multiple other transcriptional factors (TF), such as nuclear factor kappa B, E2F1 and IGF-1-dependent TFs (York et al, 2010;Ma et al, 2011;Walsh et al, 2012). By coactivating NR and these NFs, all members of the SRC family can modulate diverse genes expression programs and play important roles in growth, metabolism, reproduction and turmorigenesis (Wu et al, 2007;Coste et al, 2008;Yi et al, 2008;Cai et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Steroid Receptor Coactivator-3 Promotes Bladder Cancer Through Upregulation of CXCR4

Wang¹,

Liu²,

Qu³

2013

Asian Pacific Journal of Cancer Prevention

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The three homologous members of the p160 SRC family (SRC-1, SRC-2 and SRC-3) mediate the transcriptional functions of nuclear receptors and other transcription factors, and are the most studied of all the transcriptional co-activators. Recent work has indicated that the SRC-3 gene is subject to amplification and overexpression in various human cancers. Some of the molecular mechanisms responsible for SRC overexpression, along with the mechanisms by which SRC-3 promotes breast and prostate cancer cell proliferation and survival, have been identified. However, the function of SRC-3 in bladder cancer remains poorly understood. In the present study, our results indicate that overexpression of SRC-3 promotes bladder cancer cell proliferation whereas knockdown of SRC-3 results in inhibition. At the molecular level, we further established that CXCR4 is a transcriptional target of SRC-3. Therefore, our study first identified that SRC-3 plays a critical role in the bladder cancer, which may be a target beneficial for its prevention and treatment.

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MAD2L2 inhibits colorectal cancer growth by promoting NCOA3 ubiquitination and degradation

Chen

et al. 2018

Molecular Oncology

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Nuclear receptor coactivator 3 (NCOA3) is a transcriptional coactivator that has elevated expression in multiple tumor types, including colorectal cancer (CRC). However, the molecular mechanisms that regulate the tumorigenic functions of NCOA3 in CRC remain largely unknown. In this study, we aimed to discover and identify the novel regulatory proteins of NCOA3 and explore their mechanisms of action. Immunoprecipitation (IP) coupled with mass spectrometry (IP‐MS) analysis was used to detect, identify, and verify the proteins that interacted with NCOA3 in CRC cells. The biological functions of the candidate proteins and the underlying molecular mechanism were investigated in CRC cells and mouse model in vitro and in vivo. The clinical significance of NCOA3 and its interaction partner protein in CRC patients was also studied. We identified mitotic arrest deficient 2‐like protein 2 (MAD2L2, also known as MAD2B or REV7), with two signal peptide sequences of LIPLK and EVYPVGIFQK, to be an interaction partner of NCOA3. Overexpression of MAD2L2 suppressed the proliferation, migration, and clonogenicity of CRC cells by inducing the degradation of NCOA3. The mechanism study showed that increased MAD2L2 expression in CRC cells activated p38, which was required for the phosphorylation of NCOA3 that led to its ubiquitination and degradation by the proteasome. Moreover, we found that MAD2L2 predicted favorable prognosis in CRC patients. We have discovered a novel role of MAD2L2 in the regulation of NCOA3 degradation and proposed that MAD2L2 serves as a tumor suppressor in CRC.

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SRC-3 Coactivator Functional Lifetime Is Regulated by a Phospho-Dependent Ubiquitin Time Clock

Cited by 213 publications

References 31 publications

p38 Mitogen‐activated protein kinase‐dependent regulation of SRC‐3 and involvement in retinoic acid receptor α signaling in embryonic cortical neurons

p38 Mitogen‐activated protein kinase‐dependent regulation of SRC‐3 and involvement in retinoic acid receptor α signaling in embryonic cortical neurons

Steroid Receptor Coactivator-3 Promotes Bladder Cancer Through Upregulation of CXCR4

MAD2L2 inhibits colorectal cancer growth by promoting NCOA3 ubiquitination and degradation

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