The microphthalmia-associated transcription factor (MITF) is required for melanocyte development, maintenance of the melanocyte-specific transcription, and survival of melanoma cells. MITF positively regulates expression of more than 25 genes in pigment cells. Recently, it has been demonstrated that expression of several MITF downstream targets requires the SWI/SNF chromatin remodeling complex, which contains one of the two catalytic subunits, Brm or Brg1. Here we show that the expression of MITF itself critically requires active SWI/SNF. In several Brm/Brg1-expressing melanoma cell lines, knockdown of Brg1 severely compromised MITF expression with a concomitant downregulation of MITF targets and decreased cell proliferation. Although Brm was able to substitute for Brg1 in maintaining MITF expression and melanoma cell proliferation, sequential knockdown of both Brm and Brg1 in 501mel cells abolished proliferation. In Brg1-null SK-MEL-5 melanoma cells, depletion of Brm alone was sufficient to abrogate MITF expression and cell proliferation. Chromatin immunoprecipitation confirmed the binding of Brg1 or Brm to the promoter of MITF. Together these results demonstrate the essential role of SWI/SNF for expression of MITF and suggest that SWI/SNF may be a promissing target in melanoma therapy.
- MeSH
- aktivace transkripce MeSH
- chromozomální proteiny, nehistonové metabolismus MeSH
- DNA-helikasy metabolismus MeSH
- imunoprecipitace MeSH
- jaderné proteiny metabolismus MeSH
- lidé MeSH
- melanom genetika MeSH
- nádorové buněčné linie MeSH
- promotorové oblasti (genetika) MeSH
- regulace genové exprese u nádorů MeSH
- restrukturace chromatinu MeSH
- transkripční faktor spojený s mikroftalmií genetika MeSH
- transkripční faktory genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Melanin production is the primary mechanism protecting human skin against the UV light-induced damage. The polymeric compound melanin is synthesized within melanocytes in the specialized subcellular organelles, termed melanosomes, which are then transferred to surrounding keratinocytes. The genes for melanin synthesis and deposition are coordinately expressed in melanocytes. The transcription factor MITF, which has been reported to activate more than 25 genes in pigment cells, has emerged as an essential regulator not only for melanocyte development, proliferation and survival, but also for the expression of enzymes and structural proteins ensuring the production of melanin. MITF is a transcriptional activator of several genes which encode melanosome-localized proteins involved both in melanin synthesis and in melanosome biogenesis and transport, including genes whose mutations are associated with human oculocutaneous and ocular forms of albinism. Here, we outline the mechanisms of transcriptional regulation of genes associated with the biosynthesis of melanin in melanocytes and melanoma cells. MITF is crucial in this process, while several other factors seem to have only an auxiliary role to play under specific circumstances.
- MeSH
- biologické modely MeSH
- fyziologický stres MeSH
- lidé MeSH
- melaniny biosyntéza MeSH
- melanocyty cytologie fyziologie MeSH
- melanom genetika patofyziologie MeSH
- melanozomy fyziologie MeSH
- pigmentace kůže genetika fyziologie MeSH
- promotorové oblasti (genetika) MeSH
- sekvence nukleotidů MeSH
- trans-aktivátory genetika fyziologie MeSH
- transkripční faktor spojený s mikroftalmií genetika fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- biochemie dějiny trendy výchova MeSH
- klinická chemie MeSH
- volné radikály MeSH
- výročí a významné události MeSH
- Publikační typ
- biografie MeSH
- O autorovi
- Štípek, Stanislav, 1941- Autorita
- MeSH
- biochemie MeSH
- klinická chemie MeSH
- toxikologie MeSH
- Publikační typ
- biografie MeSH
- O autorovi
- Štípek, Stanislav, 1941- Autorita
The influence of side-chain structure on the mode of reaction of ortho-quinone amines has been investigated with a view, ultimately, to developing potential methods of therapeutic intervention by manipulating the early stages of melanogenesis. Four N-substituted dopamine derivatives have been prepared and quinone formation studied using pulse radiolysis and tyrosinase-oximetry. Ortho-quinones with an amide or urea side chain were relatively stable, although evidence for slow formation of isomeric para-quinomethanes was observed. A thiourea derivative cyclized fairly rapidly (k = 1.7/s) to a product containing a seven-membered ring, whereas a related amidine gave more rapidly (k approximately 2.5 x 10(2)/s) a stable spirocyclic product. The results suggest that cyclization of amides, ureas and carbamates (NHCO-X; X = R, NHR or OR) does not occur and is not, therefore, a viable approach to the formation of tyrosinase-activated antimelanoma prodrugs. It is also concluded that for N-acetyldopamine spontaneous ortho-quinone to para-quinomethane isomerization is slow.
- MeSH
- Agaricus enzymologie MeSH
- antitumorózní látky chemie terapeutické užití MeSH
- dopamin analogy a deriváty chemie MeSH
- financování organizované MeSH
- fungální proteiny chemie MeSH
- isomerie MeSH
- melaniny chemická syntéza chemie MeSH
- melanom enzymologie farmakoterapie MeSH
- molekulární struktura MeSH
- nádorové proteiny chemie MeSH
- oxidace-redukce MeSH
- prekurzory léčiv chemie MeSH
- tyrosinasa chemie MeSH
- MeSH
- diferenciální diagnóza MeSH
- finanční podpora výzkumu jako téma MeSH
- genetická transkripce MeSH
- imunohistochemie metody MeSH
- lidé MeSH
- melanocyty MeSH
- melanom diagnóza genetika patologie MeSH
- mikroftalmie diagnóza genetika patologie MeSH
- nádorové biomarkery diagnostické užití MeSH
- Check Tag
- lidé MeSH
