Suppressor role of activating transcription factor 2 (ATF2) in skin cancer

Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2008; 105(5):1674-9. DOI: 10.1073/pnas.0706057105
Source: PubMed


Activating transcription factor 2 (ATF2) regulates transcription in response to stress and growth factor stimuli. Here, we use a mouse model in which ATF2 was selectively deleted in keratinocytes. Crossing the conditionally expressed ATF2 mutant with K14-Cre mice (K14.ATF2(f/f)) resulted in selective expression of mutant ATF2 within the basal layer of the epidermis. When subjected to a two-stage skin carcinogenesis protocol [7,12-dimethylbenz[a]anthracene/phorbol 12-tetradecanoate 13-acetate (DMBA/TPA)], K14.ATF2(f/f) mice showed significant increases in both the incidence and prevalence of papilloma development compared with the WT ATF2 mice. Consistent with these findings, keratinocytes of K14.ATF2(f/f) mice exhibit greater anchorage-independent growth compared with ATF2 WT keratinocytes. Papillomas of K14.ATF2(f/f) mice exhibit reduced expression of presenilin1, which is associated with enhanced beta-catenin and cyclin D1, and reduced Notch1 expression. Significantly, a reduction of nuclear ATF2 and increased beta-catenin expression were seen in samples of squamous and basal cell carcinoma, as opposed to normal skin. Our data reveal that loss of ATF2 transcriptional activity serves to promote skin tumor formation, thereby indicating a suppressor activity of ATF2 in skin tumor formation.

Download full-text


Available from: Boris Fichtman, Apr 23, 2014
  • Source
    • "After a latency period of 60 weeks, ATF2 heterozygous mice develop mammary tumors spontaneously, and furthermore, low levels of ATF2 expression in human breast tumors have been reported (Maekawa et al., 2007). ATF2 also inhibits tumor development in a mouse model of skin cancer (Bhoumik et al., 2008), and deletion of ATF2 in B cells leads to a resistance to apoptosis and accelerates the onset of lymphoma in the Em-Myc mouse model (Walczynski et al., 2014). Furthermore, recent findings indicate that the SS18-SSX2 fusion protein found in human synovial sarcomas derives its oncogenicity from its ability to interact with ATF2 and to silence ATF2 target promoters (Su et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: JNK and p38 phosphorylate a diverse set of substrates and, consequently, can act in a context-dependent manner to either promote or inhibit tumor growth. Elucidating the functions of specific substrates of JNK and p38 is therefore critical for our understanding of these kinases in cancer. ATF2 is a phosphorylation-dependent transcription factor and substrate of both JNK and p38. Here, we show ATF2 suppresses tumor formation in an orthotopic model of liver cancer and cellular transformation in vitro. Furthermore, we find that suppression of tumorigenesis by JNK requires ATF2. We identify a transcriptional program activated by JNK via ATF2 and provide examples of JNK- and ATF2-dependent genes that block cellular transformation. Significantly, we also show that ATF2-dependent gene expression is frequently downregulated in human cancers, indicating that amelioration of JNK-ATF2-mediated suppression may be a common event during tumor development. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Nov 2014 · Cell Reports
  • Source
    • "These factors are members of the basic leucine zipper (bZIP) family of transcription factors. Once activated ATF2 forms a homodimer or heterodimers with cJun, or other AP1 family members and binds CREs to regulate diverse target genes including CREB1, ATF, and Jun/Fos family members [14], [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The upstream Gγ-globin cAMP-response element (G-CRE) plays an important role in regulating Gγ-globin expression through binding of ATF2 and its DNA-binding partners defined in this study. ATF2 knockdown resulted in a significant reduction of γ-globin expression accompanied by decreased ATF2 binding to the G-CRE. By contrast, stable ATF2 expression in K562 cells increased γ-globin transcription which was reduced by ATF2 knockdown. Moreover, a similar effect of ATF2 on γ-globin expression was observed in primary erythroid progenitors. To understand the role of ATF2 in γ-globin expression, chromatographically purified G-CRE/ATF2-interacting proteins were subjected to mass spectrometry analysis; major binding partners included CREB1, cJun, Brg1, and histone deacetylases among others. Immunoprecipitation assays demonstrated interaction of these proteins with ATF2 and in vivo GCRE binding in CD34(+) cells undergoing erythroid differentiation which was correlated with γ-globin expression during development. These results suggest synergism between developmental stage-specific recruitments of the ATF2 protein complex and expression of γ-globin during erythropoiesis. Microarray studies in K562 cells support ATF2 plays diverse roles in hematopoiesis and chromatin remodeling.
    Full-text · Article · Nov 2013 · PLoS ONE
  • Source
    • "The resulting tumors display enhanced β-catenin and cyclin D1 and reduced Notch1 expression. This is consistent with the observation of reduced ATF2 and increased β-catenin in human squamous and basal cell carcinoma samples [99] and suggests that ATF2 suppresses epidermal carcinogenesis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: AP1 (jun/fos) transcription factors (c-jun, junB, junD, c-fos, FosB, Fra-1, and Fra-2) are key regulators of epidermal keratinocyte survival and differentiation and important drivers of cancer development. Understanding the role of these factors in epidermis is complicated by the fact that each protein is expressed, at different levels, in multiple cells layers in differentiating epidermis, and because AP1 transcription factors regulate competing processes (i.e., proliferation, apoptosis, and differentiation). Various in vivo genetic approaches have been used to study these proteins including targeted and conditional knockdown, overexpression, and expression of dominant-negative inactivating AP1 transcription factors in epidermis. Taken together, these studies suggest that individual AP1 transcription factors have different functions in the epidermis and in cancer development and that altering AP1 transcription factor function in the basal versus suprabasal layers differentially influences the epidermal differentiation response and disease and cancer development.
    Full-text · Article · May 2013
Show more