Selective Roles for cAMP Response Element-binding Protein Binding Protein and p300 Protein as Coregulators for Androgen-regulated Gene Expression in Advanced Prostate Cancer Cells

Ianculescu, Irina; Wu, Dai-Ying; Siegmund, Kimberly D.; Stallcup, Michael R.

doi:10.1074/jbc.m111.300194

Cited by 101 publications

(67 citation statements)

References 47 publications

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“…We hypothesized that this dependence on coactivator proteins for the functional output of AR activation may present a potential point of intervention in CRPC. The highly homologous histone acetyltransferases CBP [cAMP response element binding protein (CREB) binding protein] and p300 are known coactivators of AR and have been implicated in enhancing the response to androgen (16)(17)(18). Consistent with this, CBP/p300 has been proposed to play an oncogenic role in prostate cancer, and upregulation of both proteins has been observed in tumors (19)(20)(21).…”

Section: Introductionsupporting

confidence: 48%

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Jin¹,

Garcia²,

Chan³

et al. 2017

Cancer Research

116

104

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Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castrationresistant prostate cancer. Cancer Res; 77(20); 5564-75. Ó2017 AACR.

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Section: Introductionsupporting

confidence: 48%

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Jin¹,

Garcia²,

Chan³

et al. 2017

Cancer Research

116

104

View full text Add to dashboard Cite

show abstract

“…It should also be realized that the step at which a factor binds is not always equivalent to when that factor exerts its biological effect. For example, the number of genomic binding sites for GRs is ϳ10-fold greater than the number of induced genes (59,60), there is no temporal correlation between GR binding to enhancer regions and the transcriptional response (61), p300 is recruited to the androgen-responsive elements of the TMPRSS2 and FKBP5 genes but is required for androgen induction of only TMPRSS2 (62), and paused RNA polymerase II is bound well before it is active in transcriptional elongation.…”

Section: Discussionmentioning

confidence: 99%

A Conserved Protein Motif Is Required for Full Modulatory Activity of Negative Elongation Factor Subunits NELF-A and NELF-B in Modifying Glucocorticoid Receptor-regulated Gene Induction Properties

Luo

Zhu

et al. 2013

Journal of Biological Chemistry

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Background: Understanding glucocorticoid receptor (GR)-regulated gene transcription requires detailed description of cofactor actions. Results: NELF subunits have new activities altering GR induction properties of exogenous and endogenous genes. Conclusion: NELF-A and NELF-B are decelerators functioning at two positions after GR and before/at the reporter gene site of action. Significance: Functional ordering of NELF-A and NELF-B relative to other factors in GR transactivation is determined.

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“…The number of binding sites in the genome for the glucocorticoid receptor (GR) 4 is ϳ10-fold greater than the number of induced genes (14,15). p300 is recruited by added androgen to the androgen-responsive elements of the TMPRSS2 and FKBP5 genes but is required for androgen induction of only the former gene (13). RNA polymerase II is frequently found bound to pausing sites at about 50 bp downstream from the start of transcription of the induced gene but is not engaged in elongation until a later time (16 -18).…”

mentioning

confidence: 99%

Identification of Location and Kinetically Defined Mechanism of Cofactors and Reporter Genes in the Cascade of Steroid-regulated Transactivation

Blackford

Guo

Zhu

et al. 2012

Journal of Biological Chemistry

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Background: Current descriptions of steroid hormone action are largely phenomenological rather than mechanistic. Results: Methodology is described for determining kinetically defined mechanisms and relative sites of action of any two cofactors with steroid receptors. Conclusion: Position and mode of reporter gene action are constant. Significance: Location and mechanistic action of cofactors, relative to each other and reporter, is assignable in sequence for receptor-regulated gene transactivation.

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Selective Roles for cAMP Response Element-binding Protein Binding Protein and p300 Protein as Coregulators for Androgen-regulated Gene Expression in Advanced Prostate Cancer Cells

Cited by 101 publications

References 47 publications

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

A Conserved Protein Motif Is Required for Full Modulatory Activity of Negative Elongation Factor Subunits NELF-A and NELF-B in Modifying Glucocorticoid Receptor-regulated Gene Induction Properties

Identification of Location and Kinetically Defined Mechanism of Cofactors and Reporter Genes in the Cascade of Steroid-regulated Transactivation

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