Corepressor/Coactivator Paradox: Potential Constitutive Coactivation by Corepressor Splice Variants

Xiang, Meng; Arulsundaram, Vishnuka D.; Yousef, Ahmed F.; Webb, Paul; Baxter, John D.; Mymryk, Joe S.; Walfish, Paul G.

doi:10.1621/nrs.04022

Cited by 4 publications

(3 citation statements)

References 33 publications

(47 reference statements)

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“…During retinoic-acid-induced P19 stem cell differentiation, the expression of CoAA undergoes a rapid switch to CoAM in the cavity of the embryoid body (Iwasaki et al, 2001; Auboeuf et al, 2004). Moreover, some isoforms of coregulators even exert the opposite function (Meng et al, 2006). For example, testicular zinc-finger protein (TZF) is a corepressor of androgen receptor (AR), but one of its isoforms, TZF-L, becomes a coactivator of AR (Tao et al, 2006a; Tao et al, 2006b).…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of PNRC splicing variants

Wang

Chen

et al. 2008

Gene

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Nuclear receptor (NR) dependent transcriptional action requires recruitment of diverse factors characterized as coregulators. PNRC (proline-rich nuclear receptor coregulatory protein) is a member of coregulators that are capable of potentiating the transcriptional activity of NRs. Here we identified three human PNRC splicing variants designated PNRC1c, PNRC1d and PNRC1f. PNRC1c and PNRC1f are generated through alternative recognition of the 3'-splice site in exon 1, leading to in-frame deletion of 79 amino acids aa) and an altered reading frame, respectively. PNRC1d is generated through the alternate promoter usage and forms a truncated protein containing C-terminus 142 aa of full-length PNRC. These isoforms differ in their abilities to bind NRs and potentiate NR mediated transcriptions. Moreover, PNRC1d can modulate the activity of full-length PNRC in enhancing ER mediated transcription. Our results suggest PNRC exists as functionally distinct isoforms and alternative splicing serves as a regulatory mechanism of PNRC coactivator activity.

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Section: Introductionmentioning

confidence: 99%

Identification and characterization of PNRC splicing variants

Wang

Chen

et al. 2008

Gene

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“…Interestingly, however, spliced variants of N-CoR devoid of its repressor domains can act as an activator via its intact interacting domains (CoR-NR box motifs) [52, 59]. Since the cellular context of yeast also lacks SRC-p300 complexes needed for E1A to inhibit gene activation by T3-TR, E1A functions as a TR coactivator in this model system [20, 52, 59]. Clearly, further studies are needed to clarify all the details of the mechanism.…”

Section: Discussionmentioning

confidence: 99%

The adenoviral E1A protein displaces corepressors and relieves gene repression by unliganded thyroid hormone receptors in vivo

et al. 2009

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The human adenovirus type 5 early region 1A (E1A) is one of two oncogenes present in the adenovirus genome and functions by interfering with the activities of cellular regulatory proteins. The E1A gene is alternatively spliced to yield five products. Earlier studies have revealed that E1A can regulate the function of thyroid hormone (T3) receptors (TRs). However, analysis in yeast compared with transfection studies in mammalian cell cultures yields surprisingly different effects. Here, we have examined the effect of E1A on TR function by using the frog oocyte in vivo system, where the effects of E1A can be studied in the context of chromatin. We demonstrate that different isoforms of E1A have distinct effects on TR function. The two longest forms inhibit both the repression by unliganded TR and activation by T3-bound TR. We further show that E1A binds to unliganded TR to displace the endogenous corepressor nuclear receptor corepressor, thus relieving the repression by unliganded TR. On the other hand, in the presence of T3, E1A inhibits gene activation by T3-bound TR indirectly, through a mechanism that requires its binding domain for the general coactivator p300. Taken together, our results thus indicate that E1A affects TR function through distinct mechanisms that are dependent upon the presence or absence of T3.

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“…We previously proposed that the yeast Saccharomyces cerevisiae is an excellent system in which to study NR signaling (10). Yeast lack conventional NRs and SRCs, but contain homologs of key mammalian enzymes required for chromatin modification and general transcription factors.…”

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confidence: 99%

Identification of CCR4 and other essential thyroid hormone receptor co-activators by modified yeast synthetic genetic array analysis

Govindan

Xiang

Denis

et al. 2009

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

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Identification of thyroid hormone receptor (TR) co-regulators has enhanced our understanding of thyroid hormone (TH) action. However, it is likely that many other co-regulators remained unidentified, and unbiased methods are required to discover these proteins. We have previously demonstrated that the yeast Saccharomyces cerevisiae is an excellent system in which to study TR action, and that defined TR signaling complexes in a eukaryotic background devoid of complicating influences of mammalian cell co-regulators can be constructed and analyzed for endogenous yeast genes, many of which are conserved in mammals. Here, a modified synthetic genetic array analysis was performed by crossing a yeast strain that expressed TR␤1 and the co-activator GRIP1/ SRC2 with 384 yeast strains bearing deletions of known genes. Eight genes essential for TH action were isolated, of which 4 are conserved in mammals. Examination of one, the yeast CCR4 and its human homolog CCR4/NOT6 (hCCR4), confirmed that (i) transfected CCR4 potentiates a TH response in cultured cells more efficiently than established TR co-activators and (ii) knockdown of CCR4 expression strongly inhibited a TH response (>80%). TH treatment promoted rapid and sustained hCCR4 recruitment to the TH-responsive deiodinase 1 promoter and TR co-localizes with hCCR4 in the nucleus and interacts with hCCR4 in 2-hybrid and pull-down assays. These findings indicate that a modified yeast synthetic genetic array strategy is a feasible method for unbiased identification of conserved genes essential for TR and other nuclear receptor hormone functions in mammals.nuclear receptor co-activators ͉ conserved nuclear receptor signaling genes

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Corepressor/Coactivator Paradox: Potential Constitutive Coactivation by Corepressor Splice Variants

Cited by 4 publications

References 33 publications

Identification and characterization of PNRC splicing variants

Identification and characterization of PNRC splicing variants

The adenoviral E1A protein displaces corepressors and relieves gene repression by unliganded thyroid hormone receptors in vivo

Identification of CCR4 and other essential thyroid hormone receptor co-activators by modified yeast synthetic genetic array analysis

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