Mutation of the POU-Specific Domain of Pit-1 and Hypopituitarism Without Pituitary Hypoplasia

Pfäffle, Roland; DiMattia, Gabriel E.; Parks, John S.; Brown, Milton R.; Wit, Jan M.; Jansen, M.; Nat, Hans van der; Brande, J. L. Van den; Rosenfeld, Michael G.; Ingraham, Holly A.

doi:10.1126/science.257.5073.1118

Cited by 428 publications

(199 citation statements)

References 19 publications

Supporting

Mentioning

193

Contrasting

Unclassified

Order By: Relevance

“…The mutation disrupts the ability of Pit-1 to activate transcription from prolactin and growth hormone DNA response elements, but has only a minimal effect on DNA binding (Pfaffle et al 1992). Intriguingly, the mutation is located in a region (amino acids 33-41) showing the most variation in structure, when comparing the Pit-1 POU-specific domains with each other and with Oct-1.…”

Section: Cphdmentioning

confidence: 99%

See 1 more Smart Citation

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.

193

144

View full text Add to dashboard Cite

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:

show abstract

Section: Cphdmentioning

confidence: 99%

“…A more puzzling mutation is A158P, which maps to helix a2 of the POU-specific domain (Pfaffle et al 1992). The mutation disrupts the ability of Pit-1 to activate transcription from prolactin and growth hormone DNA response elements, but has only a minimal effect on DNA binding (Pfaffle et al 1992).…”

Section: Cphdmentioning

confidence: 99%

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.

193

144

View full text Add to dashboard Cite

show abstract

“…It was initially identified and cloned based on its ability to bind and transactivate the expression of the mammalian prl and gh genes. These findings were underscored by the identification of spontaneous mutations in the human and murine pit1 gene, which cause an absence of lacto-, thyro-, and somatotrope differentiation, thereby defining the so-called Pit1 lineage (Li et al, 1990, Tatsumi et al, 1992, Pfaffle et al, 1992, Radovick et al, 1992. The more recently identified zebrafish pit1 mutants lack exactly the same three AH cell types, indicating that the function of Pit1 during AH lineage specification is highly conserved among the different vertebrate classes (Nica et al, 2004).…”

mentioning

confidence: 99%

How to make a teleost adenohypophysis: Molecular pathways of pituitary development in zebrafish

Pogoda

Hammerschmidt

2009

Molecular and Cellular Endocrinology

View full text Add to dashboard Cite

Please cite this article as: Pogoda, H.-M., Hammerschmidt, M., How to make a Teleost Adenohypophysis: Molecular Pathways of Pituitary development in Zebrafish, Molecular and Cellular Endocrinology (2008), doi:10.1016/j.mce.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In the past years, the zebrafish has emerged as a powerful tool to elucidate the genetic networks controlling vertebrate development, behavior and disease. Based on mutants isolated in forward genetic screens and on gene knock-downs using morpholino oligonucleotide (oligo) antisense technology, our current understanding of the molecular machinery driving adenohypophyseal ontogeny could be considerably improved. In addition, comparative analyses have shed further light onto the evolution of this rather recently invented organ. The goal of this review is to summarize current knowledge of the genetic and molecular control of zebrafish pituitary development, with special focus on most recent findings, including some thus far unpublished data from our own laboratory on the transcription factor Six1. In addition, zebrafish data will be discussed in comparison with current understanding of adenohypophysis development in mouse.

show abstract

“…Os camundongos Snell e Jackson, modelos animais de pan-hipopituitarismo, apresentam alterações no Pit-1 (29). Pacientes com pan-hipopituitarismo por mutação no PIT-1 foram descritos por diversos grupos em 1992 (30)(31)(32)(33). Várias mutações no PIT-1 têm sido reconhecidas em casos esporádicos e em famílias afetadas com pan-hipopituitarismo (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44).…”

Section: Pit-1unclassified

“…Pacientes com pan-hipopituitarismo por mutação no PIT-1 foram descritos por diversos grupos em 1992 (30)(31)(32)(33). Várias mutações no PIT-1 têm sido reconhecidas em casos esporádicos e em famílias afetadas com pan-hipopituitarismo (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). A herança pode ser autossômica recessiva, causada por mutações em homozigose ou heterozigose composta, que produzem vários graus de perda de ligação ao DNA ou perda da ativação da transcrição (31,32,(34)(35)(36)40,45).…”

Section: Pit-1unclassified

Bases Genéticas dos Distúrbios de Crescimento

Marui

Souza

Carvalho

et al. 2002

Arq Bras Endocrinol Metab

View full text Add to dashboard Cite

A integridade do eixo GHRH-GH-IGF-I é fundamental para o crescimento normal de um indivíduo. Mutações nos genes responsáveis por cada uma das etapas deste eixo resultam em baixa estatura grave. Podemos dividir os distúrbios de crescimento em: 1. Deficiência de GH associada a deficiências de outros hormônios hipofisários por alterações em fatores de transcrição envolvidos na organogênese hipofisária (HESX1/RPX, LHX3 e LHX4, PROP-1, PIT-1); 2. Deficiência isolada de GH (receptor do GHRH:GHRHR, GH-1, GH bioinativo); e 3. Insensibilidade ao GH (receptor de GH:GHR, gene da IGF-I e receptor da IGF-I:IGFR). Serão discutidos também os genes implicados na baixa estatura da Síndrome de Turner (SHOX) e Síndrome de Noonan (PTPN11). Atualmente estamos analisando no Laboratório de Hormônios e Genética Molecular da Disciplina de Endocrinologia da FMUSP - LIM 42 os genes HESX-1, LHX3, LHX4, PROP-1, GHRHR, GH-1, GHR, SHOX e PTPN11 em pacientes com baixa estatura e características clínicas e laboratoriais que sugerem o envolvimento destes genes.

show abstract

Mutation of the POU-Specific Domain of Pit-1 and Hypopituitarism Without Pituitary Hypoplasia

Cited by 428 publications

References 19 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.

How to make a teleost adenohypophysis: Molecular pathways of pituitary development in zebrafish

Bases Genéticas dos Distúrbios de Crescimento

Contact Info

Product

Resources

About