title: A role for ATF2 in regulating MITF and melanoma development.
abstract: The transcription factor ATF2 has been shown to attenuate melanoma susceptibility to apoptosis and to promote its ability to form tumors in xenograft models. To directly assess ATF2's role in melanoma development, we crossed a mouse melanoma model (Nras(Q61K)::Ink4a⁻/⁻) with mice expressing a transcriptionally inactive form of ATF2 in melanocytes. In contrast to 7/21 of the Nras(Q61K)::Ink4a⁻/⁻ mice, only 1/21 mice expressing mutant ATF2 in melanocytes developed melanoma. Gene expression profiling identified higher MITF expression in primary melanocytes expressing transcriptionally inactive ATF2. MITF downregulation by ATF2 was confirmed in the skin of Atf2⁻/⁻ mice, in primary human melanocytes, and in 50% of human melanoma cell lines. Inhibition of MITF transcription by MITF was shown to be mediated by ATF2-JunB-dependent suppression of SOX10 transcription. Remarkably, oncogenic BRAF (V600E)-dependent focus formation of melanocytes on soft agar was inhibited by ATF2 knockdown and partially rescued upon shMITF co-expression. On melanoma tissue microarrays, a high nuclear ATF2 to MITF ratio in primary specimens was associated with metastatic disease and poor prognosis. Our findings establish the importance of transcriptionally active ATF2 in melanoma development through fine-tuning of MITF expression.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Meera
authors.initials: M
authors.lastname: Shah
authors.forename: Anindita
authors.initials: A
authors.lastname: Bhoumik
authors.forename: Vikas
authors.initials: V
authors.lastname: Goel
authors.forename: Antimone
authors.initials: A
authors.lastname: Dewing
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Breitwieser
authors.forename: Harriet
authors.initials: H
authors.lastname: Kluger
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
authors.forename: Maryla
authors.initials: M
authors.lastname: Krajewska
authors.forename: Jason
authors.initials: J
authors.lastname: Dehart
authors.forename: Eric
authors.initials: E
authors.lastname: Lau
authors.forename: David M
authors.initials: DM
authors.lastname: Kallenberg
authors.forename: Hyeongnam
authors.initials: H
authors.lastname: Jeong
authors.forename: Alexey
authors.initials: A
authors.lastname: Eroshkin
authors.forename: Dorothy C
authors.initials: DC
authors.lastname: Bennett
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.forename: Nic
authors.initials: N
authors.lastname: Jones
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D051698:Activating Transcription Factor 2; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse