The microphthalmia-associated transcription factor (MITF) promotes melanocyte differentiation and cell cycle

The microphthalmia-associated transcription factor (MITF) promotes melanocyte differentiation and cell cycle arrest. specific MITF target genes and resistance to cisplatin. Down-regulation of the solitary ATPase BRM in SK-MEL5 cells inhibited manifestation of both differentiation specific and pro-proliferative MITF target genes and inhibited tumorigenicity in vitro. Our data suggest that heterogeneous SWI/SNF complexes composed of either the BRG1 or BRM subunit promote manifestation of unique and overlapping MITF target genes and that at least one ATPase is required for melanoma tumorigenicity. Intro Microphthalmia-associated transcription element (MITF) the expert regulator of melanocyte differentiation promotes melanocyte lineage survival and plays a key part in melanoma progression. MITF is a basic helix loop helix leucine zipper transcripton element that binds to a conserved M A-419259 package in the promoters of tyrosinase and additional melanocyte specific genes that regulate melanin synthesis and melanosome structure (Hemesath et al. 1994 MITF also promotes manifestation of genes that regulate melanoma proliferation and survival and has been termed a “lineage survival oncogene ” being amplified in 10-20% of human being melanomas (Garraway et al. 2005 The part that MITF plays in melanoma has been controversial. MITF can inhibit proliferation by directly activating manifestation of the cyclin dependent kinase inhibitors p21CIP1 and p16INK4A (Carreira et al. 2005 Loercher et al. 2005 MITF can also promote survival and proliferation by activating anti-apoptotic factors BCL2 and MLIAP (Dynek et al. 2008 McGill et al. 2002 TBX2 (Carreira et al. 2000 and the cell cycle dependent kinase CDK2 (Du et al. 2004 It has been proposed the levels of MITF determine whether MITF promotes differentiation and cell cycle arrest or proliferation (Carreira et al. 2006 In addition signaling pathways and relationships with additional regulatory proteins may regulate MITF activity. We have previously identified that MITF interacts with SWI/SNF chromatin redesigning enzymes to activate differentiation specific genes (de la Serna et al. 2006 SWI/SNF enzymes are ATP dependent multisubunit complexes that disrupt histone-DNA contacts and promote chromatin structural changes (Sif 2004 Mammalian SWI/SNF complexes are composed of the BRG1 or BRM catalytic ATPase subunit and 9-12 BRG1/BRM connected factors (BAFs). BRG1 and BRM have overlapping functions but are not always interchangeable and may interact with unique transcription factors in vitro (Kadam et al. 2000 Heterogeneous SWI/SNF complexes generated by the alternative presence of either the BRG1 or BRM ATPase as well as by a specific BAF composition may have distinct functions. For example BRG1 and BRM can differentially regulate gene manifestation (Blossoms et al. 2009 Xu et al. 2007 and SWI/SNF complexes containing either the BAF250A or BAF250B subunit have opposing tasks in cell cycle rules (Nagl et Rabbit polyclonal to ICSBP. al. 2007 As a result SWI/SNF subunit composition is an important determinant of SWI/SNF specificity. BRG1 and BRM and additional A-419259 components of the SWI/SNF complex have been implicated in malignancy. BRG1 or BRM manifestation is definitely down-regulated in a wide array of human being cancers. Loss of both BRM and BRG1 manifestation correlates with poor prognosis of non-small cell lung malignancy (Fukuoka et al. 2004 Reisman et al. 2003 Additional SWI/SNF parts are mutated erased or not indicated in many human being tumor cell lines (Decristofaro et A-419259 al. 2001 Inactivating mutations in the INI1 subunit occur in the majority of malignant rhabdoid tumors (Versteege et al. 1998 Re-introduction of SWI/SNF subunits into malignancy cells that lack manifestation induces a flat cell morphology cell cycle arrest apoptosis or senescence with reversion of the transformed phenotype indicating that loss of SWI/SNF function contributes to tumorigenicity (Dunaief et al. 1994 Wang et al. 2005 Conversely components of the SWI/SNF complex interact with the androgen receptor A-419259 to promote androgen dependent prostate.