Identification of a Transactivation Function in the Progesterone Receptor That Interacts with the TAFII110 Subunit of the TFIID Complex

Schwerk, Christian; Klotzbücher, Michael; Sachs, Martin M.; Ulber, Verena; Klein-Hitpaß, Ludger

doi:10.1074/jbc.270.36.21331

Cited by 52 publications

(19 citation statements)

References 52 publications

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“…First, AR DBD and the Nterminal part of hinge region, which are sufficient for interaction with SNURF, do not appear to possess an autonomous transcription activation function (this work and our unpublished results). In view of this, it is interesting that Schwerk et al (64) have reported that there is a weak transactivation domain within the DBD of PR which mediates the interaction between hPR and TAF II 110 in vitro. These investigators also suggested that this interaction is an important step in the PR-mediated transactivation process.…”

Section: Discussionmentioning

confidence: 99%

“…Even though the DBDs of steroid receptors appear to be mainly involved in DNA binding and homodimerization of receptor monomers, there is evidence that this domain also serves as an interaction interface for other proteins (11,41,56,64). To extend our understanding of the role of the DBD in androgen action, we conducted a yeast two-hybrid screening rAR and pM-rAR encoding full-length rAR-LexA fusions were constructed by transferring the BamHI/PstI fragment of rAR from pGEM-3Z-rAR (51) into pLex-a and pM.…”

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confidence: 99%

“…In addition to direct contacts between nuclear receptors and basal transcription factors such as TFIIB (14,25,35) and TFIIF (49), interactions with TATA-binding protein (TBP) or TBP-associated factors, TAF II s, have been described (36,50,63,64). TAF II s are suggested to function as mediators between enhancer-bound receptor and basal transcription factors (36,50,63,64). Functionally distinct TFIID complexes, comprising common and unique TAF subunits, may be responsible for specific interactions between TFIID and different activators of transcription (19,20,61).…”

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confidence: 99%

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Identification of a Novel RING Finger Protein as a Coregulator in Steroid Receptor-Mediated Gene Transcription

Moilanen

Poukka

Karvonen

et al. 1998

Molecular and Cellular Biology

198

211

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Using the DNA-binding domain of androgen receptor (AR) as a bait in a yeast two-hybrid screening, we have identified a small nuclear RING finger protein, termed SNURF, that interacts with AR in a hormonedependent fashion in both yeast and mammalian cells. Physical interaction between AR and SNURF was demonstrated by coimmunoprecipitation from cell extracts and by protein-protein affinity chromatography. Rat SNURF is a highly hydrophilic protein consisting of 194 amino acid residues and comprising a consensus C 3 HC 4 zinc finger (RING) structure in the C-terminal region and a bipartite nuclear localization signal near the N terminus. Immunohistochemical experiments indicated that SNURF is a nuclear protein. SNURF mRNA is expressed in a variety of human and rat tissues. Overexpression of SNURF in cultured mammalian cells enhanced not only androgen, glucocorticoid, and progesterone receptor-dependent transactivation but also basal transcription from steroid-regulated promoters. Mutation of two of the potential Zn 2؉ coordinating cysteines to serines in the RING finger completely abolished the ability of SNURF to enhance basal transcription, whereas its ability to activate steroid receptor-dependent transcription was maintained, suggesting that there are separate domains in SNURF that mediate interactions with different regulatory factors. SNURF is capable of interacting in vitro with the TATA-binding protein, and the RING finger domain is needed for this interaction. Collectively, we have identified and characterized a ubiquitously expressed RING finger protein, SNURF, that may function as a bridging factor and regulate steroid receptor-dependent transcription by a mechanism different from those of previously identified coactivator or integrator proteins.Androgen receptor (AR) that mediates the biological actions of physiological androgens is a member of the superfamily of ligand-inducible transcription factors (59). Like other nuclear receptors, AR contains three major structural and interchangeable domains: the N-terminal transactivation domain, the central DNA-binding domain (DBD) that associates with specific androgen response elements (AREs) in target genes, and the C-terminal ligand binding domain (LBD) that binds physiological and synthetic androgens. Upon ligand binding, AR acquires a new conformational state (39), which enables the receptor to interact with AREs and converts the protein to a transcriptional activator. Molecular analyses have shown that the N-terminal half of AR, similar to that of other steroid receptors, contains sequences responsible for the activation function AF-1 (11,34,37,47,54,59,65). In addition to AF-1, another activation function (AF-2) has been identified in the LBDs of various nuclear receptors, including AR (11, 51). Besides encompassing nuclear localization signal (NLS) (38,65,75), the functional role of the hinge region residing between the DBDs and LBDs of steroid receptors has remained elusive.Nuclear receptors have been shown to contact the basal transcription machinery,...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Identification of a Novel RING Finger Protein as a Coregulator in Steroid Receptor-Mediated Gene Transcription

Moilanen

Poukka

Karvonen

et al. 1998

Molecular and Cellular Biology

198

211

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“…Based upon mutational analyses and the crystal structure of the highly homologous glucocorticoid receptor (GR) DBD, residues located in the second zinc finger are postulated to make contact with proteins bound at the activated transcription complex (Schena et al 1989, Hard et al 1990, Luisi et al 1991. In fact, it has been shown that at least one transcription factor, a TATA-binding protein (TBP)-associated factor-TAFII 110 , interacts directly with the DBD of PR (Schwerk et al 1995).…”

Section: Introductionmentioning

confidence: 99%

Association of the Ku autoantigen/DNA-dependent protein kinase holoenzyme and poly(ADP-ribose) polymerase with the DNA binding domain of progesterone receptors

Sartorius¹,

Takimoto²,

Richer³

et al. 2000

Journal of Molecular Endocrinology

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Ligand-activated progesterone receptors (PR) bind to DNA at specific progesterone response elements by means of a DNA binding domain (DBD PR ) containing two highly conserved zinc fingers. DNA-bound PRs regulate transcription via interaction with other nuclear proteins and transcription factors. We have now identified four HeLa cell nuclear proteins that copurify with a glutathionine-S-transferase-human DBD PR fusion protein.Microsequence and immunoblot analyses identified one of these proteins as the 113 kDa poly(ADPribose) polymerase. The three other proteins were identified as subunits of the DNA-dependent protein kinase (DNA-PK) holoenzyme: its DNA binding regulatory heterodimers consisting of Ku70 and Ku86, and the 460 kDa catalytic subunit, DNA-PK CS . DNA-PK that was 'pulleddown' by DBD PR on the affinity resin was able to (1) autophosphorylate Ku70, Ku86, and DNA-PK CS , (2) transphosphorylate DBD PR , and (3) phosphorylate a DNA-PK-specific p53 peptide substrate. DNA-PK was also able to associate with the DBD of the yeast activator GAL4. However, neither a PR DBD mutant lacking a structured first zinc finger (DBD CYS ) nor the core DBD of the estrogen receptor (DBD ER ) copurified DNA-PK, suggesting the interaction is not non-specific for DBDs. Lastly, we found that DNA-PK copurified with full-length human PR transiently expressed in HeLa cells, suggesting that the human PR/ DNA-PK complex can assemble in vivo. These data show that DNA-PK and DBD PR interact, that DBD PR is a phosphorylation substrate of DNA-PK, and suggest a potential role for DNA-PK in PR-mediated transcription.

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“…This has been shown most extensively for the TFIID complex, where different activators interact with distinct TBPassociated factors (TAFs) which represent coactivator proteins (27). Steroid receptors such as the estrogen and progesterone receptors have been reported to interact with human TAF II 30 and Drosophila TAF II 110, respectively (35,63). Several putative coactivators that interact with the C-terminal transactivation domains in the ligand binding domains of one or more nuclear receptors have been identified.…”

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Role of Hydrophobic Amino Acid Clusters in the Transactivation Activity of the Human Glucocorticoid Receptor

Almlöf

Gustafsson

Wright

1997

Molecular and Cellular Biology

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We have performed a mutagenesis analysis of the 58-amino-acid 1-core peptide, which represents the core transactivation activity of the 1 transactivation domain from the glucocorticoid receptor. Mutants with altered activity were identified by phenotypic screening in the yeast Saccharomyces cerevisiae. Most mutants with reduced activity had substitutions of hydrophobic amino acids. Most single-substitution mutants with reduced activity were localized near the N terminus of the 1-core within a segment that has been shown previously to have a propensity for ␣-helix conformation, suggesting that this helical region is of predominant importance. The particular importance of hydrophobic residues within this region was confirmed by comparing the activities of alanine substitutions of the hydrophobic residues in this and two other helical regions. The hydrophobic residues were shown to be important for the transactivation activity of both the isolated 1-core and the intact glucocorticoid receptor in mammalian cells. Rare mutations in helical regions I and II gave rise to increased transcriptional activation activity. These mutations increase the hydrophobicity of hydrophobic patches on each of these helices, suggesting a relationship between the hydrophobicity of the patches and transactivation activity. However, certain nonhydrophobic residues are also important for activity. Interestingly, helical region I partially matches a consensus motif found in the retinoic acid receptor, VP16, and several other activator proteins.The glucocorticoid receptor (GR) is a member of a large family of ligand-inducible nuclear transcription factors. Binding of glucocorticoids causes dissociation of the receptor from an inactive complex containing hsp90, allowing translocation into the nucleus and subsequent binding to specific glucocorticoid-responsive elements (GREs) present within glucocorticoid-regulated genes (4,20,30). The GR has a modular structure such that different functions, including ligand binding, DNA binding, and transactivation, are performed by discrete domains within the receptor protein. Initially two regions, 1 (residues 77 to 262) and 2 (residues 526 to 556), were implicated in the post-DNA-binding transactivation activity of the human GR (25, 31). These segments retain activity even when removed from their normal receptor context. 1 is the more active of the two transactivation domains (31), and it has recently been shown that a 58-amino-acid peptide (the 1-core) retains most of the activity of the intact 1 domain in the yeast Saccharomyces cerevisiae (14). In addition, a third region near the C terminus of the receptor protein that is highly conserved between different receptors has been suggested to play a role in the transactivation activity of the GR (17).Accurate initiation of transcription at RNA polymerase II promoters involves the assembly of a transcription complex that consists of RNA polymerase II and a number of basal transcription factors,

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Identification of a Transactivation Function in the Progesterone Receptor That Interacts with the TAFII110 Subunit of the TFIID Complex

Cited by 52 publications

References 52 publications

Identification of a Novel RING Finger Protein as a Coregulator in Steroid Receptor-Mediated Gene Transcription

Identification of a Novel RING Finger Protein as a Coregulator in Steroid Receptor-Mediated Gene Transcription

Association of the Ku autoantigen/DNA-dependent protein kinase holoenzyme and poly(ADP-ribose) polymerase with the DNA binding domain of progesterone receptors

Role of Hydrophobic Amino Acid Clusters in the Transactivation Activity of the Human Glucocorticoid Receptor

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