title: A Transcriptionally Inactive ATF2 Variant Drives Melanomagenesis.
abstract: Melanoma is one of the most lethal cutaneous malignancies, characterized by chemoresistance and a striking propensity to metastasize. The transcription factor ATF2 elicits oncogenic activities in melanoma, and its inhibition attenuates melanoma development. Here, we show that expression of a transcriptionally inactive form of Atf2 (Atf2(Δ8,9)) promotes development of melanoma in mouse models. Atf2(Δ8,9)-driven tumors show enhanced pigmentation, immune infiltration, and metastatic propensity. Similar to mouse Atf2(Δ8,9), we have identified a transcriptionally inactive human ATF2 splice variant 5 (ATF2(SV5)) that enhances the growth and migration capacity of cultured melanoma cells and immortalized melanocytes. ATF2(SV5) expression is elevated in human melanoma specimens and is associated with poor prognosis. These findings point to an oncogenic function for ATF2 in melanoma development that appears to be independent of its transcriptional activity.
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Claps
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Yann
authors.initials: Y
authors.lastname: Cheli
authors.affiliation: Division of Cancer Epidemiology and Genetics, Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Tongwu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Marzia
authors.initials: M
authors.lastname: Scortegagna
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lau
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Hyungsoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Qi
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Li
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: James
authors.affiliation: Department of Dermatology, University of Zürich, University of Zürich Hospital, Zürich 8091, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dzung
authors.affiliation: Department of Dermatology, University of Zürich, University of Zürich Hospital, Zürich 8091, Switzerland.
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Levesque
authors.affiliation: Department of Dermatology, University of Zürich, University of Zürich Hospital, Zürich 8091, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.affiliation: Departments of Dermatology and Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.affiliation: Division of Cancer Epidemiology and Genetics, Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: zeev@ronailab.net.
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics*; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D009506:Nevus / Q000235:genetics / Q000473:pathology; D009857:Oncogenes; D048493:Proto-Oncogene Proteins B-raf / Q000172:deficiency / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D051698:Activating Transcription Factor 2; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf