Deutsch
 
Hilfe Datenschutzhinweis Impressum
  DetailsucheBrowse

Datensatz

DATENSATZ AKTIONENEXPORT
  Point mutations in GLI3 lead to misregulation of its subcellular localization

Krauß, S., So, J., Hambrock, M., Köhler, A., Kunath, M., Scharff, C., et al. (2009). Point mutations in GLI3 lead to misregulation of its subcellular localization. PLoS ONE, 4, e7471-e7471. doi:10.1371/journal.pone.0007471.

Item is

Externe Referenzen

einblenden:

Urheber

einblenden:
ausblenden:
 Urheber:
Krauß, Sybille1, Autor
So, Joyce2, Autor           
Hambrock, Melanie3, Autor           
Köhler, Andrea, Autor
Kunath, Melanie1, Autor
Scharff, Constance2, Autor           
Wessling, Martina, Autor
Grzeschik, Karl-Heinz, Autor
Schneider, Rainer2, Autor           
Schweiger, Susann2, Autor           
Affiliations:
1Max Planck Society, ou_persistent13              
2Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              
3Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              

Inhalt

einblenden:
ausblenden:
Schlagwörter: -
 Zusammenfassung: Background Mutations in the transcription factor GLI3, a downstream target of Sonic Hedgehog (SHH) signaling, are responsible for the development of malformation syndromes such as Greig-cephalopolysyndactyly-syndrome (GCPS), or Pallister-Hall-syndrome (PHS). Mutations that lead to loss of function of the protein and to haploinsufficiency cause GCPS, while truncating mutations that result in constitutive repressor function of GLI3 lead to PHS. As an exception, some point mutations in the C-terminal part of GLI3 observed in GCPS patients have so far not been linked to loss of function. We have shown recently that protein phosphatase 2A (PP2A) regulates the nuclear localization and transcriptional activity a of GLI3 function. Principal Findings We have shown recently that protein phosphatase 2A (PP2A) and the ubiquitin ligase MID1 regulate the nuclear localization and transcriptional activity of GLI3. Here we show mapping of the functional interaction between the MID1-α4-PP2A complex and GLI3 to a region between amino acid 568-1100 of GLI3. Furthermore we demonstrate that GCPS-associated point mutations, that are located in that region, lead to misregulation of the nuclear GLI3-localization and transcriptional activity. GLI3 phosphorylation itself however appears independent of its localization and remains untouched by either of the point mutations and by PP2A-activity, which suggests involvement of an as yet unknown GLI3 interaction partner, the phosphorylation status of which is regulated by PP2A activity, in the control of GLI3 subcellular localization and activity. Conclusions The present findings provide an explanation for the pathogenesis of GCPS in patients carrying C-terminal point mutations, and close the gap in our understanding of how GLI3-genotypes give rise to particular phenotypes. Furthermore, they provide a molecular explanation for the phenotypic overlap between Opitz syndrome patients with dysregulated PP2A-activity and syndromes caused by GLI3-mutations.

Details

einblenden:
ausblenden:
Sprache(n): eng - English
 Datum: 2009-10-15
 Publikationsstatus: Erschienen
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Art des Abschluß: -

Veranstaltung

einblenden:

Entscheidung

einblenden:

Projektinformation

einblenden:

Quelle 1

einblenden:
ausblenden:
Titel: PLoS ONE
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 4 Artikelnummer: - Start- / Endseite: e7471 - e7471 Identifikator: ISSN: 1932-6203