Pit-1 binding to specific DNA sites as a monomer or dimer determines gene-specific use of a tyrosine-dependent synergy domain.

Holloway, Jeffrey M.; Szeto, Daniel P.; Scully, Kathleen M.; Glass, Christopher K.; Rosenfeld, Michael G.

doi:10.1101/gad.9.16.1992

Cited by 92 publications

(64 citation statements)

References 80 publications

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“…Similarily, Oct-1 and Oct-2 have been shown to interact with the activator OCA-B but only on a subset of octamer containing sites (Luo and Roeder 1995;Gstaiger et al 1996). Likewise, interactions with distinct putative coactivators may occur when Pit-I is bound as a monomer or as a dimer to its specific DNA response elements (Holloway et al 1995). Therefore, the same POU-domain protein may be used in different contexts on different DNA elements to achieve gene-specific action.…”

Section: Genes and Developmentmentioning

confidence: 99%

“…The third key mechanism for understanding POU domain flexibility relates to their ability to bind DNA as both monomers and homo-and heterodimers (Kemler et al 1989;LeBowitz et al 1989;Poellinger and Roeder 1989;Ingraham et al 1990;Voss et al 1991;Holloway et al 1995). Pit-I loses ~1200A^ of solvent accessible surface area attributable to dimerization on DNA.…”

Section: Genes and Developmentmentioning

confidence: 99%

“…The sequences of these sites vary widely around a weak consensus sequence (A/T)(A/T)TATNCAT, raising the intriguing possibility that Pit-1 might be configured differently on the different sites. Most of these sites bind Pit-1 as a dimer, although the prolactin Prl-ID site accommodates Pit-1 as a monomer (Ingraham et al 1990; Holloway et al 1995). This differential binding can lead to alternative uses of the synergistic activation domains (Holloway et al 1995).…”

mentioning

confidence: 99%

“…Most of these sites bind Pit-1 as a dimer, although the prolactin Prl-ID site accommodates Pit-1 as a monomer (Ingraham et al 1990; Holloway et al 1995). This differential binding can lead to alternative uses of the synergistic activation domains (Holloway et al 1995). Oct-1 was identified originally by its recognition of the conserved octamer motif TAAAG-CAT found in the promoters of a number of tissue-specific and ubiquitously expressed genes (Wegner et al 1993;Herr and Cleary 1995).…”

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confidence: 99%

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Structure of Pit-1 POU domain bound to DNA as a dimer: unexpected arrangement and flexibility.

Jacobson¹,

Leon-Del-Rio²,

Rosenfeld³

et al. 1997

Genes Dev.

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195

145

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Pit-1, a member of the POU domain family of transcription factors, characterized by a bipartite DNA-binding domain, serves critical developmental functions based on binding to diverse DNA elements in its target genes. Here we report a high resolution X-ray analysis of the Pit-1 POU domain bound to a DNA element as a homodimer. This analysis reveals that Pit-1 subdomains bind to perpendicular faces of the DNA, rather than opposite faces of the DNA as in Oct-1. This is accomplished by different spacing and orientation of the POU-specific domain. Contrary to previous predictions, the dimerization interface involves the carboxyl terminus of the DNA recognition helix of the homeodomain, which in an extended conformation interacts with specific residues at the amino terminus of helix al and in the loop between helices a3 and a4 of the POU-specific domain of the symmetry related monomer. These features suggest the molecular basis of disease-causing mutations in Pit-1 and provide potential basis for the flexible allostery between protein domains and DNA sites in the activation of target genes.[Key Words: Crystal structure; Pit-1; POU-domain factors; dimerization; spacing; orientation] Received October 25, 1996; revised version accepted December 3, 1996.The expression of specific genes in cells is often governed by families of transcription factors harboring DNA-binding motifs. In eukaryotes, these factors often exhibit extraordinary versatility. For instance, the bZip and helix-loop-helix families of transcription factors bind to DNA as both homo-and heterodimers (Bexevanis and Vinson 1993;Glover and Harrison 1995). The nuclear receptors go a step further and recognize DNA elements with different spacings and polarities between the half-sites (Naar et al. 1991;Umesono et al. 1991;Kurokawa et al. 1993). The POU domain family of transcription factors are perhaps the most remarkable in their ability to bind DNA as both monomers and dimers and in their ability to adopt diverse configurations (Wegner et al. 1993;Herr and Cleary 1995). Part of this versatility derives from their unusual bipartite structure, consisting of a highly conserved -75 amino acid POUspecific domain (POUg), tethered by a linker of variable length and composition, to a 60-amino-acid homeodomain (POUH). The flexibility of the linker, in particular, allows the possibility of different relative spacings and orientations between the subdomains. This helps to exThese authors contributed equally to this work. "Corresponding author. Present address:

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Section: Genes and Developmentmentioning

confidence: 99%

Section: Genes and Developmentmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Structure of Pit-1 POU domain bound to DNA as a dimer: unexpected arrangement and flexibility.

Jacobson¹,

Leon-Del-Rio²,

Rosenfeld³

et al. 1997

Genes Dev.

Self Cite

195

145

View full text Add to dashboard Cite

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“…The DNA element thus dictates the configurations of subdomains and subsequent recruitment of specific coregulators to control transcription (25). Specifically, the ability of Pit-1 to bind to DNA as either a monomer or a dimer dictates the domains that it uses to synergize with heterologous transcription factors (26). Similarly, the spacing of the contact points for the POU-specific domain and POU homeodomain is sufficient to transform Pit-1 from a trans-activating factor to a repressor (27).…”

mentioning

confidence: 99%

Ras Signaling and Transcriptional Synergy at a Flexible Ets-1/Pit-1 Composite DNA Element Is Defined by the Assembly of Selective Activation Domains

Duval

Jean

Gutierrez‐Hartmann

2003

Journal of Biological Chemistry

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Pit-1 and Ets-1 binding to a composite element synergistically activates and targets Ras-mitogen-activated protein kinase signaling to the rat prolactin promoter. These transcriptional responses appear to depend on three molecular features: organization of the Ets-1/Pit-1 composite element, physical interaction of these two factors via the Pit-1 homeodomain (amino acids 199 -291) and the Ets-1 regulatory III domain (amino acids 190 -257), and assembly of their transcriptional activation domains (TADs). Here we show that the organization of the Ets-1/Pit-1 composite element tolerates significant flexibility with regard to Ras stimulation and synergy. Specifically, the putative monomeric Pit-1 binding site can be substituted with bona fide binding sites for either a Pit-1 monomer or dimer, and these sites tolerated a separation of 28 bp. Additionally, we show that the physical interaction of Ets-1 and Pit-1 is not required for Ras responsiveness or synergy because block mutations of the Pit-1 interaction surface in Ets-1, which reduced Ets-1/Pit-1 binding in vitro, did not significantly affect Ets-1 stimulation of Ras responsiveness or synergy. We also show differential use of distinct TAD subtypes and Pit-1 TAD subregions to mediate either synergy or Ras responsiveness. Specifically, TADs from Gal4, VP16, or Ets-2 regulatory III domain linked to Ets-1 DNA binding domain constructs restored synergy to these TAD/Ets-1 DNA binding domain fusions. Conversely, deletion of the defined Pit-1 TAD (amino acids 2-80) retained synergy, but not Ras responsiveness. Consequently, we further defined the Pit-1 amino-terminal TAD into region 1 (R1, amino acids 2-45) and region 2 (R2, amino acids 46 -80). R1 appears to regulate basal and synergistic responses, whereas the Ras response was mapped to R2. In summary, Ras responsiveness and Pit-1/Ets-1 synergy are mediated through the assembly of distinct TADs at a flexible composite element, indicating that different mechanisms underlie these two transcriptional responses and that the Pit-1 R2 subregion represents a novel, tissue-specific Ras-responsive TAD.

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Regulation of Growth Hormone Gene Expression

Cooke

Liebhaber

1999

Comprehensive Physiology

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The sections in this article are: Transcriptional Controls Growth Hormone Gene Organization Activation of Proximal Promoter Elements of the Growth Hormone Gene in Somatotropes Structure and Function of the Proximal Promoter Activation of Placentally Expressed Human Growth Hormone Genes Role of Silencer Elements Genetic Evidence for Transcriptional Control and Developmental Pathways Posttranscriptional Controls Alternative Splicing of Human Growth Hormone Genes Alternative Splicing of the Bovine Growth Hormone Gene m RNA Stability

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Pit-1 binding to specific DNA sites as a monomer or dimer determines gene-specific use of a tyrosine-dependent synergy domain.

Cited by 92 publications

References 80 publications

Structure of Pit-1 POU domain bound to DNA as a dimer: unexpected arrangement and flexibility.

Structure of Pit-1 POU domain bound to DNA as a dimer: unexpected arrangement and flexibility.

Ras Signaling and Transcriptional Synergy at a Flexible Ets-1/Pit-1 Composite DNA Element Is Defined by the Assembly of Selective Activation Domains

Regulation of Growth Hormone Gene Expression

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