The Steroid Receptor Coactivator-1 Contains Multiple Receptor Interacting and Activation Domains That Cooperatively Enhance the Activation Function 1 (AF1) and AF2 Domains of Steroid Receptors

Oñate, Sergio A.; Boonyaratanakornkit, Viroj; Spencer, Thomas E.; Tsai, Sophia Y.; Tsai, Ming‐Jer; Edwards, Dean P.; O’Malley, Bert W.

doi:10.1074/jbc.273.20.12101

Cited by 376 publications

(285 citation statements)

References 54 publications

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“…Analogous to other members of nuclear receptor superfamily, the androgen receptor contains a DNA-binding domain and a C-terminal ligand-binding domain functioning as liganddependent nuclear receptors with activation functions 1 and 2 (AF-1 and AF-2) transcription activation domains (2)(3)(4). The integrity of the C-terminal AF-2 domain and recruitment of many cofactors including histone acetyltransferase (HAT)-containing proteins and the TRIP͞DRIP͞ARC complex are important for the transcriptional regulation.…”

mentioning

confidence: 99%

Ligand-specific allosteric regulation of coactivator functions of androgen receptor in prostate cancer cells

Baek

Ohgi

Nelson

et al. 2006

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

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The androgen receptor not only mediates prostate development but also serves as a key regulator of primary prostatic cancer growth. Although initially responsive to selective androgen receptor modulators (SARMs), which cause recruitment of the nuclear receptor-corepressor (N-CoR) complex, resistance invariably occurs, perhaps in response to inflammatory signals. Here we report that dismissal of nuclear receptor-corepressor complexes by specific signals or androgen receptor overexpression results in recruitment of many of the cohorts of coactivator complexes that permits SARMs and natural ligands to function as agonists. SARM-bound androgen receptors appear to exhibit failure to recruit specific components of the coactivators generally bound by liganded nuclear receptors, including cAMP response element-binding protein (CBP)͞p300 or coactivator-associated arginine methyltransferase 1 (CARM1) to the SARM-bound androgen receptor, although still causing transcriptional activation of androgen receptor target genes. SARM-bound androgen receptors use distinct LXXLL (L, leucine; X, any amino acid) helices in the p160 nuclear receptor interaction domains that may impose selective allosteric effects, providing a component of the molecular basis of differential responses to different classes of ligands by androgen receptor.corepressor ͉ nuclear receptor-corepressor ͉ methyltransferase

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mentioning

confidence: 99%

Ligand-specific allosteric regulation of coactivator functions of androgen receptor in prostate cancer cells

Baek

Ohgi

Nelson

et al. 2006

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

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“…Values were expressed as the mean7s.d. of triplicate samples (Onate et al, 1998). As shown in Figure 3a, the AREs luciferase activity was induced 22-fold by R1881, eightfold by IL-4, and 431-fold by the mixture of R1881 and 50 ng/ml of IL-4.…”

Section: Il-4 Activates Armentioning

confidence: 85%

Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway

et al. 2003

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Androgen receptor (AR) plays an important role in the development and progression of prostate cancer upon the action of androgen through the binding of the androgenresponsive elements (AREs) on the target genes. Abnormal activation of the AR by nonandrogen has been implicated in the progression of androgen-independent prostate cancer. The levels of interleukin-4 (IL-4) are significantly elevated in sera of patients with hormone refractory prostate cancer. The potential role of IL-4 on the activation of AR was investigated in prostate cancer cells. IL-4 enhances AR-mediated prostate-specific antigen (PSA) expression and ARE-containing gene activity through activation of the AR in the androgen ablation condition in human prostate cancer cells. The AR can also be sensitized by IL-4 and activated by significantly lower levels of androgen (10 pm of R1881) in prostate cancer cells. IL-4 enhances nuclear translocation of AR and increases binding of the AR to the ARE in LNCaP prostate cancer cells. Blocking of the Akt pathway by an Akt-specific inhibitor LY294002 abrogates IL-4-induced PSA expression and AR signaling. These results demonstrate that IL-4 enhances PSA expression through activation of the AR and Akt signaling pathways in LNCaP prostate cancer cells. Understanding IL-4-induced signaling leading to abnormal activation of AR will provide insights into the molecular mechanisms of androgen-independent progression of prostate cancer cells.

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“…3), is devoid of activation domains but does contain a HAT activity domain and a RID (9,48). This segment also displays a dominant negative repressor activity (4,46,66), which appears to be due simply to its ability to bind tightly to the receptor LBD, thereby blocking the binding of other coactivators (48).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Induction Properties of Glucocorticoid Receptor-Agonist and -Antagonist Complexes by Coactivators Involves Binding to Receptors but Is Independent of Ability of Coactivators to Augment Transactivation

He¹,

Szapary²,

Simons

2002

Journal of Biological Chemistry

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Coactivators such as TIF2 and SRC-1 modulate the positioning of the dose-response curve for agonistbound glucocorticoid receptors (GRs) and the partial agonist activity of antiglucocorticoid complexes. These properties of coactivators differ from their initially defined activities of binding to, and increasing the total levels of transactivation by, agonist-bound steroid receptors. We now report that constructs of TIF2 and SRC-1 lacking the two activation domains (AD1 and AD2) have significantly less ability to increase transactivation but retain most of the activity for modulating the dose-response curve and partial agonist activity. Mammalian two-hybrid experiments show that the minimum TIF2 segment with modulatory activity (TIF2.4) does not interact with p300, CREB-binding protein, or PCAF, which also modulates GR activities. DRIP150 and DRIP205 have been implicated in coactivator actions but are unable to modulate GR activities. The absence of synergism by PCAF or DRIP150 with SRC-1 or TIF2, respectively, further suggests that these other factors are not involved. The ability of a TIF2.4 fragment (i.e. TIF2.37), which is not known to interact with proteins, to block the actions of TIF2.4 suggests that an unidentified binder mediates the modulatory activity of TIF2. Pull-down experiments with GST/TIF2.4 demonstrate a direct interaction of TIF2 with GR in a hormone-dependent fashion that requires the receptor interaction domains of TIF2 and is equally robust with agonists and most antiglucocorticoids. These observations, which are confirmed in mammalian two-hybrid assays, suggest that the capacity of coactivators such as TIF2 to modulate the partial agonist activity of antisteroids is mediated by the binding of coactivators to GR-antagonist complexes. In conclusion, the modulatory activity of coactivators with GR-agonist and -antagonist complexes is mechanistically distinct from the ability of coactivators to augment the total levels of transactivation and appears to involve the binding to both GR-steroid complexes and an unidentified TIF2-associated factor(s).

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The Steroid Receptor Coactivator-1 Contains Multiple Receptor Interacting and Activation Domains That Cooperatively Enhance the Activation Function 1 (AF1) and AF2 Domains of Steroid Receptors

Cited by 376 publications

References 54 publications

Ligand-specific allosteric regulation of coactivator functions of androgen receptor in prostate cancer cells

Ligand-specific allosteric regulation of coactivator functions of androgen receptor in prostate cancer cells

Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway

Modulation of Induction Properties of Glucocorticoid Receptor-Agonist and -Antagonist Complexes by Coactivators Involves Binding to Receptors but Is Independent of Ability of Coactivators to Augment Transactivation

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