Selective Phosphorylations of the SRC-3/AIB1 Coactivator Integrate Genomic Reponses to Multiple Cellular Signaling Pathways

Wu, Ray-Chang; Qin, Jun; Yi, Ping; Wong, Jiemin; Tsai, Sophia Y.; Tsai, Ming‐Jer; O’Malley, Bert W.

doi:10.1016/j.molcel.2004.08.019

Cited by 287 publications

(357 citation statements)

References 31 publications

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“…MBG increases the activities of Src kinase, ERK1/2 and GSK3 in muscle cells [32], and several of these signaling molecules (e.g. ERK1/2 and GSK3) can affect the activity of SRC-3 [18].…”

Section: Discussionmentioning

confidence: 98%

“…The MR is a phosphoprotein whose transcriptional activity can be regulated by signaling pathways [31], and recent work demonstrates that the activity of coactivators such as SRC-3 is modulated by post-translational modifications [26]. Indeed, loss of SRC-3 phosphorylation results in poor stimulation of receptor-dependent gene expression, and reduced interaction with the CBP coactivator [18]. Thus, intracellular signaling pathways originating from distinct classes of molecules can have profound influences on MR and SRC-3 function and consequently steroid receptor-dependent gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…The marinobufagenin (MBG) was a gift from Dr. G. Robert Pettit, Arizona State University, Department of Biological Sciences. The mammalian expression plasmid for human mineralocorticoid receptor (pRShMR [16]) was a gift from Dr. Ronald Evans (Salk Institute, San Diego, CA), and vectors for ERα [pCR3.1-hERα [17]] and Flag-epitope-tagged SRC-3 [pCMV-Flag-SRC-3 [18]] were described previously as were the synthetic target genes, PRE-E1b-Luc (a PR and MR responsive reporter [19]) and EREE1b-Luc [17].…”

Section: Chemicals and Plasmid Dnasmentioning

confidence: 99%

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Marinobufagenin interferes with the function of the mineralocorticoid receptor

Smith

Huang

et al. 2007

Biochemical and Biophysical Research Communications

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Marinobufagenin (MBG) is a cardiotonic steroid of the bufadienolide class of compounds which has the ability to inhibit the ubiquitous enzyme, Na + /K + -ATPase, resulting in natriuresis. The involvement of MBG in the pathogenesis of volume expansion-mediated forms of hypertension has been suggested for some time, and we have proposed that MBG participates in the hypertension noted in preeclampsia. We examined the hypothesis that MBG might contribute to these forms of hypertension by promoting the activity of the mineralocorticoid receptor (MR). However, our data demonstrate that instead, MBG interferes with the functioning of the MR by inhibiting the transcriptional activity of the receptor, and this is reflected in a reduced interaction between the SRC-3 coactivator and the MR. Thus, the ability of MBG to cause a natriuresis may be due, not only to inhibition of Na + /K + -ATPase activity, but also its ability to interfere with MR-dependent expression of the Na/K/H exchanger in the late distal nephron.

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“…MBG increases the activities of Src kinase, ERK1/2 and GSK3 in muscle cells [32], and several of these signaling molecules (e.g. ERK1/2 and GSK3) can affect the activity of SRC-3 [18].…”

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Chemicals and Plasmid Dnasmentioning

confidence: 99%

See 1 more Smart Citation

Marinobufagenin interferes with the function of the mineralocorticoid receptor

Smith

Huang

et al. 2007

Biochemical and Biophysical Research Communications

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“…Phosphorylation of coregulators seems to be the key regulatory mechanism that controls the localization, specificity, and function of coregulators and probably allow coregulators to sense the physiologic signals (42). It seems that PELP1 has the capacity to sense a wide variety of signals, and phosphorylation may allow PELP1 to cross-talk between NRs and growth factor pathways.…”

Section: Discussionmentioning

confidence: 99%

Growth Factor Regulation of Estrogen Receptor Coregulator PELP1 Functions via Protein Kinase A Pathway

Nagpal

Nair

Chakravarty

et al. 2008

Molecular Cancer Research

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PELP1 (proline-rich, glutamic acid -rich, and leucine-rich protein-1) is a potential proto-oncogene that functions as a coregulator of estrogen receptor (ER), and its expression is deregulated during breast cancer progression. Emerging evidence suggests growth factor signaling crosstalk with ER as one possible mechanism by which breast tumors acquire resistance to therapy. In this study, we examined mechanisms by which growth factors modulate PELP1 functions, leading to activation of ER. Using in vivo labeling assays, we have found that growth factors promote phosphorylation of PELP1. Utilizing a panel of substrate-specific phosphorylated antibodies, we discovered that growth factor stimulation promotes phosphorylation of PELP1 that is recognized by a protein kinase A (PKA) substrate -specific antibody. Accordingly, growth factor -mediated PELP1 phosphorylation was effectively blocked by PKA-specific inhibitor H89. Utilizing purified PKA enzyme and in vitro kinase assays, we obtained evidence of direct PELP1 phosphorylation by PKA. Using deletion and mutational analysis, we identified PELP1 domains that are phosphorylated by PKA. Interestingly, site-directed mutagenesis of the putative PKA site in PELP1 compromised growth factor -induced activation and subnuclear localization of PELP1 and also affected PELP1-mediated transactivation function. Utilizing MCF-7 cells expressing a PELP1 mutant that cannot be phosphorylated by PKA, we provide mechanistic insights by which growth factor signaling regulates ER transactivation in a PELP1-dependent manner. Collectively, these findings suggest that growth factor signals promote phosphorylation of ER coactivator PELP1 via PKA pathway, and such modification may have functional implications in breast tumors with deregulated growth factor signaling. (Mol Cancer Res 2008;6(5):851 -61)

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“…SRC-3 is involved in normal breast development and implicated in orchestrating the expression of hundreds of genes involved in growth signaling pathways in breast tissue [28]. It is amplified in 5-10% and overexpressed in 30-60% of primary breast cancers [26,29], and its expression correlates with ERa and PR positivity and tumor size [30].…”

Section: Estrogen Receptor Cofactors and Breast Cancermentioning

confidence: 99%