PA1 Protein, a New Competitive Decelerator Acting at More than One Step to Impede Glucocorticoid Receptor-mediated Transactivation

Zhang, Zhenhuan; Sun, Yunguang; Cho, Young Wook; Chow, Carson C.; Simons, S. Stoney

doi:10.1074/jbc.m112.427740

Cited by 20 publications

(60 citation statements)

References 62 publications

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“…It is generally believed that transiently transfected genes are not good models for receptor-regulated gene expression because they do not possess the same level of chromatin organization (55,63). However, the similar effects of factor on gene induction and GR recruitment to endogenous and exogenous genes both in the present study and in earlier studies (29) suggest that situations exist where the two systems may be studied interchangeably.…”

Section: Discussioncontrasting

confidence: 41%

“…This assay does not require any prior knowledge of the mechanism of action of the competing factors (29). In fact, any mechanism by which the factor influences GR activity will be detected.…”

Section: Discussionmentioning

confidence: 99%

“…6B. This means, as described previously (29), that NELF-B is a competitive decelerator acting at n ϭ 2 locations at or before the CLS. Furthermore, because two competitive decelerators cannot act at the same site according to the theory on which the assay is based (10,12,13), NELF-B must either act at the CLS and at another site before the CLS or act at two different sites before the CLS.…”

Section: Application Of Competition Assay To Determine Actions Of Nelmentioning

confidence: 99%

“…First, we asked whether NELF-B can reverse the effects of the accelerator TIF2 (14,29). As shown in Fig.…”

Section: Comparison Of Actions Of Nelf-b and Nelf-a Inmentioning

confidence: 99%

“…Positive results with both synthetic and endogenous GR-regulated genes prompted us to investigate NELF-B effects on GR binding to enhancers. Our recently developed competition assay (13,14,29) was used to determine the kinetically determined mode and site of action of wild type and mutant NELF-B and NELF-A. We conclude that NELF-B and NELF-A are new GR cofactors that act independently, but additively, as a competitive decelerator (14), each at two different steps.…”

mentioning

confidence: 99%

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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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Section: Discussioncontrasting

confidence: 41%

Section: Discussionmentioning

confidence: 99%

Section: Application Of Competition Assay To Determine Actions Of Nelmentioning

confidence: 99%

“…First, we asked whether NELF-B can reverse the effects of the accelerator TIF2 (14,29). As shown in Fig.…”

Section: Comparison Of Actions Of Nelf-b and Nelf-a Inmentioning

confidence: 99%

mentioning

confidence: 99%

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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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Bi‐allelic PAGR1 variants are associated with microcephaly and a severe neurodevelopmental disorder: Genetic evidence from two families

Daum

Ganapathi

Hirsch³

et al. 2021

American J of Med Genetics Pt A

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Exome and genome sequencing were used to identify the genetic etiology of a severe neurodevelopmental disorder in two unrelated Ashkenazi Jewish families with three affected individuals. The clinical findings included a prenatal presentation of microcephaly, polyhydramnios and clenched hands while postnatal findings included microcephaly, severe developmental delay, dysmorphism, neurologic deficits, and death in infancy. A shared rare homozygous, missense variant (c.274A > G; p.Ser92Gly, NM_024516.4) was identified in PAGR1, a gene currently not associated with a Mendelian disease. PAGR1 encodes a component of the histone methyltransferase MLL2/ MLL3 complex and may function in the DNA damage response pathway. Complete knockout of the murine Pagr1a is embryonic-lethal. Given the available evidence, PAGR1 is a strong candidate gene for a novel autosomal recessive severe syndromic neurodevelopmental disorder.

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Loss of function of mouse Pax‐Interacting Protein 1‐associated glutamate rich protein 1a (Pagr1a) leads to reduced Bmp2 expression and defects in chorion and amnion development

Kumar

Lualdi

Lončarek

et al. 2014

Developmental Dynamics

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Background Human PAX-Interacting Protein 1 (PAXIP1)-associated glutamate rich protein 1 (PAGR1, also known as PA1) originally was discovered as part of a complex containing PAXIP1 and histone H3K4 methyltransferases MLL3 and MLL4, suggesting a role in epigenetic gene regulation. Further in vitro studies suggested additional functions in DNA damage repair and transcription. However, in vivo analysis of PAGR1 function has been lacking. Results Here we show that expression of the cognate mouse gene Pagr1a is found predominately in the extraembryonic and chorionic ectoderm from pregastrulation stages and is up-regulated within the embryo proper after gastrulation. Embryos with a germ line deletion of Pagr1a establish the anterior–posterior axis, and show normal neuroectodermal, mesodermal, and endodermal patterning, but fail to develop beyond the four- to five-somite stage or to undergo axial rotation. Pagr1a−/− embryos also show abnormal development of extraembryonic tissues with defects seen in the amnion, chorion and visceral yolk sac. At the molecular level, Pagr1a−/− embryos have reduced expression of BMP2, a known regulator of extraembryonic development. Conclusions Loss of mouse Pagr1a function leads to defective extraembryonic development, likely due at least in part to altered BMP signaling, contributing to developmental arrest.

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PA1 Protein, a New Competitive Decelerator Acting at More than One Step to Impede Glucocorticoid Receptor-mediated Transactivation

Cited by 20 publications

References 62 publications

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

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

Bi‐allelic PAGR1 variants are associated with microcephaly and a severe neurodevelopmental disorder: Genetic evidence from two families

Loss of function of mouse Pax‐Interacting Protein 1‐associated glutamate rich protein 1a (Pagr1a) leads to reduced Bmp2 expression and defects in chorion and amnion development

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