Nejvíce citovaný článek - PubMed ID 11886515
Transcriptional repression of the microphthalmia gene in melanoma cells correlates with the unresponsiveness of target genes to ectopic microphthalmia-associated transcription factor
Metastasized malignant melanoma has a poor prognosis because of its intrinsic resistance to chemotherapy and radiotherapy. The central role in the melanoma transcriptional network has the transcription factor MITF (microphthalmia-associated transcription factor). It has been shown recently that the expression of MITF and some of its target genes require the SWI/SNF chromatin remodeling complex. Here we demonstrate that survival of melanoma cells requires functional SWI/SNF complex not only by supporting expression of MITF and its targets and but also by activating expression of prosurvival proteins not directly regulated by MITF. Microarray analysis revealed that besides the MITF-driven genes, expression of proteins like osteopontin, IGF1, TGFß2 and survivin, the factors known to be generally associated with progression of tumors and the antiapoptotic properties, were reduced in acute BRG1-depleted 501mel cells. Western blots and RT-PCR confirmed the microarray findings. These proteins have been verified to be expressed independently of MITF, because MITF depletion did not impair their expression. Because these genes are not regulated by MITF, the data suggests that loss of BRG1-based SWI/SNF complexes negatively affects survival pathways beyond the MITF cascade. Immunohistochemistry showed high expression of both BRM and BRG1 in primary melanomas. Exogenous CDK2, osteopontin, or IGF1 each alone partly relieved the block of proliferation imposed by BRG1 depletion, implicating that more factors, besides the MITF target genes, are involved in melanoma cell survival. Together these results demonstrate an essential role of SWI/SNF for the expression of MITF-dependent and MITF-independent prosurvival factors in melanoma cells and suggest that SWI/SNF may be a potential and effective target in melanoma therapy.
- MeSH
- apoptóza genetika MeSH
- chromozomální proteiny, nehistonové genetika metabolismus MeSH
- cyklin-dependentní kinasa 2 genetika metabolismus MeSH
- DNA-helikasy genetika metabolismus MeSH
- imunohistochemie MeSH
- inhibitory apoptózy genetika metabolismus MeSH
- insulinu podobný růstový faktor I genetika metabolismus MeSH
- jaderné proteiny genetika metabolismus MeSH
- lidé MeSH
- melanom genetika metabolismus patologie MeSH
- nádorové buněčné linie MeSH
- névus genetika metabolismus patologie MeSH
- osteopontin genetika metabolismus MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- proliferace buněk MeSH
- RNA interference MeSH
- sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
- stanovení celkové genové exprese MeSH
- survivin MeSH
- transformující růstový faktor beta2 genetika metabolismus MeSH
- transkripční faktor spojený s mikroftalmií genetika metabolismus MeSH
- transkripční faktory genetika metabolismus MeSH
- viabilita buněk genetika MeSH
- western blotting MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- BIRC5 protein, human MeSH Prohlížeč
- CDK2 protein, human MeSH Prohlížeč
- chromozomální proteiny, nehistonové MeSH
- cyklin-dependentní kinasa 2 MeSH
- DNA-helikasy MeSH
- inhibitory apoptózy MeSH
- insulinu podobný růstový faktor I MeSH
- jaderné proteiny MeSH
- MITF protein, human MeSH Prohlížeč
- osteopontin MeSH
- SMARCA2 protein, human MeSH Prohlížeč
- SMARCA4 protein, human MeSH Prohlížeč
- survivin MeSH
- SWI-SNF-B chromatin-remodeling complex MeSH Prohlížeč
- transformující růstový faktor beta2 MeSH
- transkripční faktor spojený s mikroftalmií MeSH
- transkripční faktory MeSH
