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: 9.81). 03/2008; 105(5):1674-9. DOI: 10.1073/pnas.0706057105
Source: PubMed

ABSTRACT 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.

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Available from: Boris Fichtman, Apr 23, 2014
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    • "Suppression of mammary tumors by ATF2 is associated with activation of tumor suppressor genes Maspin and GADD45a (Maekawa et al., 2008). In keratinocytes, the loss of ATF2 promotes the tumor formation, suggesting a tumor suppressor role of ATF2 in skin (Bhoumik et al., 2008). Genetic variants of the ATF-2 gene were also detected in 5 of the 46 (10.6%) lung cancers (Woo et al., 2002). "
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    ABSTRACT: Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug associated with anti-tumorigenic and pro-apoptotic properties in animal and in vitro models of cancer. However, the underlying cellular mechanisms by which TA exerts its effects are only partially understood. Activating transcription factor 3 (ATF3) is a member of the ATF/CREB subfamily of the basic region-leucine zipper family and has been known as a tumor suppressor in human colorectal cancer cells. The present study was performed to observe whether ATF3 mediates TA-induced apoptosis and to elucidate the molecular mechanism of ATF3 transcription induced by TA. TA treatment and ectopic expression of ATF3 increased apoptosis, whereas knockdown of ATF3 resulted in significant repression of TA-activated apoptosis. The TA treatment also induced ATF3 promoter activity. Internal deletion and point mutation of the predicted ATF/C/EBP binding site in ATF3 promoter abolished luciferase activation by TA. Overexpression of ATF2 resulted in significant increase in ATF3 promoter activity, and electrophoretic mobility shift assay identified this region as a core sequence to which ATF2 binds. TA treatment resulted in an increase in ATF2 phosphorylation, which was followed by a subsequent increase in ATF3 transcription. Knock down of ATF2 abolished TA-induced ATF3 expression. We further provide evidence that TA leads to increases in phospho-p38 MAPK, JNK and ERK levels. Inhibition of these pathways using selective inhibitors and dominant negative constructs ameliorated TA-induced ATF3 expression and promoter activities. The current study shows that TA stimulates ATF3 expression and subsequently induces apoptosis. These pathways are mediated through phosphorylation of ATF2, which is mediated by p38 MAPK-, JNK- and ERK-dependent pathways.
    Oncogene 09/2010; 29(37):5182-92. DOI:10.1038/onc.2010.251 · 8.56 Impact Factor
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    • "The work of others suggests that Ras pathway inhibition by ATF2 is likely not restricted to the avian system. ATF2-null keratinocytes are more susceptible to transformation by oncogenic Ras than wild-type cells (Bhoumik et al., 2008). Further examination of the mechanism(s) of ATF2 regulation of Ras activity will likely provide greater insight into the role of ATF2 in oncogenesis. "
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    ABSTRACT: Cell transformation by the v-rel oncogene is mediated by the aberrant expression of genes that are normally tightly regulated by other Rel/NF-kappaB family members. Although a number of genes inappropriately activated or suppressed by v-Rel have been identified, their contributions to the v-Rel transformation process have been poorly characterized. Here, we examine the role of individual AP-1 proteins in v-Rel-mediated transformation. v-Rel-transformed cells exhibit elevated RNA and protein expression of c-Fos, c-Jun and ATF2 and sustained repression of Fra-2. c-Fos and c-Jun are essential in both the initiation and maintenance of v-Rel-mediated transformation, whereas Fra-2 is dispensable. By employing a c-Jun dimerization mutant, we further identified Fos/Jun heterodimers as major contributors to the v-Rel transformation process. The inability of c-Rel to induce the expression of c-Fos and c-Jun contributes to its weaker oncogenic potential relative to v-Rel. Our studies also demonstrate that v-Rel may induce AP-1 members by directly upregulating gene expression (c-fos and ATF2) and by activating pathways that stimulate AP-1 activity. Although elevated expression of ATF2 is also required for v-Rel-mediated transformation, its ectopic overexpression is inhibitory. Investigating the mode of ATF2 regulation revealed a positive feedback mechanism whereby ATF2 induces p38 MAPK phosphorylation to further induce its own activity. In addition, these studies identified Ha-Ras as an effector of v-Rel-mediated transformation and reveal a novel role for ATF2 in the inhibition of the Ras-Raf-MEK-ERK signaling pathway. Overall, these studies reveal distinct and complex roles of AP-1 proteins in Rel/NF-kappaB oncogenesis.
    Oncogene 09/2010; 29(35):4925-37. DOI:10.1038/onc.2010.239 · 8.56 Impact Factor
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