A dominant negative mutant of microphthalmia transcription factor (MITF) lacking two transactivation domains suppresses transcription mediated by wild type MITF and a hyperactive MITF derivative
Jazyk angličtina Země Dánsko Médium print
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
14717844
DOI
10.1046/j.1600-0749.2003.00108.x
PII: 108
Knihovny.cz E-zdroje
- MeSH
- aktivace transkripce fyziologie MeSH
- DNA vazebné proteiny genetika metabolismus MeSH
- dominantní geny MeSH
- genetická transkripce fyziologie MeSH
- herpes simplex virus - protein Vmw65 genetika metabolismus MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- promotorové oblasti (genetika) fyziologie MeSH
- regulace genové exprese enzymů fyziologie MeSH
- rekombinantní proteiny genetika metabolismus MeSH
- suprese genetická fyziologie MeSH
- terciární struktura proteinů genetika fyziologie MeSH
- transkripční faktor spojený s mikroftalmií MeSH
- transkripční faktory genetika metabolismus MeSH
- tyrosinasa genetika metabolismus MeSH
- umělá fúze genů MeSH
- virové geny genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA vazebné proteiny MeSH
- herpes simplex virus - protein Vmw65 MeSH
- MITF protein, human MeSH Prohlížeč
- Mitf protein, mouse MeSH Prohlížeč
- rekombinantní proteiny MeSH
- transkripční faktor spojený s mikroftalmií MeSH
- transkripční faktory MeSH
- tyrosinasa MeSH
Microphthalmia transcription factor (MITF) positively regulates transcription of differentiation-related genes in several cell lineages, including melanocytes. Recent data also indicate a new important role for MITF as a factor that appears to be required for survival of melanoma cells, suggesting a possibility that abrogation of MITF function in transformed melanocytes could lead to a decreased survival via attenuating anti-apoptotic signals. Therefore, to gain a better understanding of the role which MITF plays in melanoma cell survival, it is important to find efficient means of abolishing the transactivation of its target genes. Recently, a dominant negative MITF lacking the N-terminus has been shown to down-regulate tyrosinase and Trp1 expression in normal melanocytes and mouse B16 melanoma cells. Here, a dominant negative mutant of the melanocyte-specific isoform of MITF is described carrying deletions of both N- and C-terminal transactivation domains. Cotransfection of this mutant resulted in a complete inhibition of the wild type MITF function as tested on both the reporter-linked tyrosinase promoter and an endogenous, ectopic MITF-triggered tyrosinase gene in U2-OS cells. The dominant negative construct also strongly repressed the activity of a hyperactive MITF-Vp16 chimera. Importantly, deletion of both activation domains was necessary to eliminate the residual transcription activity observed when only the N-terminal domain was removed and to achieve the repressive effect in human melanoma cells. If the activity of MITF plays a role in the long-term survival of malignant melanocytes, overexpression of a strong dominant negative MITF mutant might be a useful strategy to suppress its transactivation function.
Citace poskytuje Crossref.org