AP-1 dimers regulate transcription of the p14/p19ARF tumor suppressor gene

Ameyar-Zazoua, Maya; Wisniewska, M.; Bakiri, Latifa; Wagner, Erwin F.; Yaniv, Moshe; Weitzman, Jonathan B

doi:10.1038/sj.onc.1208424

Cited by 40 publications

(18 citation statements)

References 58 publications

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“…ARF promoter upon oncogenic signaling in human cervical carcinoma cells (32). Our results confirm that FosB, JunB, and JunD bind to the putative AP-1 site in the HLJ1 enhancer.…”

Section: Discussionsupporting

confidence: 75%

Synergistic Activation of the Tumor Suppressor, HLJ1, by the Transcription Factors YY1 and Activator Protein 1

et al. 2007

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HLJ1 is a novel tumor and invasion suppressor that inhibits tumorigenesis and cancer metastasis. However, the mechanism of HLJ1 activation is currently unclear. Here, we identify an enhancer segment in the HLJ1 gene at À2,125 to À1,039 bp upstream of the transcription start site. A 50-bp element between À1,492 and À1,443 bp is the minimal enhancer segment, which includes the activator protein 1 (AP-1) site (À1,457 to À1,451 bp), an essential regulatory domain that binds the transcriptional factors FosB, JunB, and JunD. Chromatin immunoprecipitation assays confirm that these AP-1 family members bind to a specific site in the HLJ1 enhancer segment in vivo. Overexpression of either YY1 at promoter or AP-1 at enhancer results in a 3-fold increase in the transcriptional activity of HLJ1. We propose a novel mechanism whereby expression of the tumor suppressor, HLJ1, is upregulated via enhancer AP-1 binding to promoter YY1 and the coactivator, p300, through DNA bending and multiprotein complex formation. The combined expression of AP-1 and YY1 enhances HLJ1 expression by more than five times and inhibits in vitro cancer cell invasion. Elucidation of the regulatory mechanism of HLJ1 expression may facilitate the development of personalized therapy by inhibiting cancer cell proliferation, angiogenesis, and metastasis. [Cancer Res 2007;67(10):4816-26]

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“…ARF promoter upon oncogenic signaling in human cervical carcinoma cells (32). Our results confirm that FosB, JunB, and JunD bind to the putative AP-1 site in the HLJ1 enhancer.…”

Section: Discussionsupporting

confidence: 75%

Synergistic Activation of the Tumor Suppressor, HLJ1, by the Transcription Factors YY1 and Activator Protein 1

et al. 2007

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“…The only E2F target gene that we found induced by Snf5 depletion was p19 ARF . However, additional regulators of p19 ARF have been identified, i.e., both activators (DMP-1, AP1) and transcriptional repressors (Bmi-1, Tbx2, Tbx3, and Twist) (2,31,34,42,43). Thus, it remains unclear whether Snf5 disruption activates p19 ARF via E2F.…”

Section: Vol 26 2006mentioning

confidence: 99%

Increased DNA Damage Sensitivity and Apoptosis in Cells Lacking the Snf5/Ini1 Subunit of the SWI/SNF Chromatin Remodeling Complex

Klochendler-Yeivin

Picarsky

Yaniv

2006

Molecular and Cellular Biology

Self Cite

107

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The gene encoding the SNF5/Ini1 core subunit of the SWI/SNF chromatin remodeling complex is a tumor suppressor in humans and mice, with an essential role in early embryonic development. To investigate further the function of this gene, we have generated a Cre/lox-conditional mouse line. We demonstrate that Snf5 deletion in primary fibroblasts impairs cell proliferation and survival without the expected derepression of most retinoblastoma protein-controlled, E2F-responsive genes. Furthermore, Snf5-deficient cells are hypersensitive to genotoxic stress, display increased aberrant mitotic features, and accumulate phosphorylated p53, leading to elevated expression of a specific subset of p53 target genes, suggesting a role for Snf5 in the DNA damage response. p53 inactivation does not rescue the proliferation defect caused by Snf5 deficiency but reduces apoptosis and strongly accelerates tumor formation in Snf5-heterozygous mice.Chromatin-remodeling complexes modulate nucleosome structure in an ATP-dependent manner (40, 49). The 2-MDa multisubunit SWI/SNF complex was the first such complex identified in yeast and is highly conserved among eukaryotes (14, 54). Mammalian SWI/SNF complexes are heterogenous but have several common subunits, including SNF5 (Ini1), BAF155/BAF170, and one of the highly homologous ATPase subunits (Brm or Brg1) (46,72). SWI/SNF complexes play important roles in transcriptional regulation (both activation and repression) and contribute to the control of diverse cellular processes, such as proliferation and differentiation (21,39,44,59,63). Gene-targeting experiments with mice have shown that the mammalian SWI/SNF complex is essential for early embryonic development, since homozygous inactivation of genes encoding different subunits (Brg1, Snf5, or Swi3/Srg3) results in peri-implantation lethality (11,22,37,38,57).Accumulating genetic evidence has defined SNF5/Ini1 as a tumor suppressor gene in humans and mice. Homozygous inactivating mutations or deletions in the SNF5 gene in humans are associated with malignant rhabdoid and atypical teratoid/ rhabdoid tumors (7, 62, 69). These are rare, but very aggressive, pediatric tumors that arise primarily in the brain and kidney. Furthermore, we and others have shown that Snf5 functions as a tumor suppressor gene in mice. Heterozygous Snf5 ϩ/Ϫ animals develop tumors at a high incidence via loss of heterozygosity (LOH) at the Snf5 locus. These tumors share histological features with their human counterparts and develop at very specific sites, mainly in the nervous system (22, 38, 57). Recently, it was shown that mice with a reversible conditional mutation of Snf5 developed early, and fully penetrant, T-cell lymphomas (58). Several studies have also revealed that Brg1 is mutated or deleted in a variety of human tumor cell lines (74). Mice heterozygous for a Brg1-null mutation are cancer prone and develop tumors of epithelial origin without loss of heterozygosity (11).It is still unclear whether the tumor suppressor function of Snf5 depends on SWI/SNF act...

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“…Similarly, AP-1 has been shown to play important roles in RAS-induced cellular transformation (Johnson et al 1996). Finally, AP-1 heterodimers have been shown to cooperate with RAS to activate the ARF promoter (Ameyar-Zazoua et al 2005). We therefore suggest a model (Fig.…”

Section: Ink4amentioning

confidence: 99%

The H3K27me3 demethylase JMJD3 contributes to the activation of theINK4A–ARFlocus in response to oncogene- and stress-induced senescence

Agger¹,

Cloos²,

Rudkjær³

et al. 2009

Genes Dev.

400

360

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The tumor suppressor proteins p16INK4A and p14ARF, encoded by the INK4A–ARF locus, are key regulators of cellular senescence. The locus is epigenetically silenced by the repressive H3K27me3 mark in normally growing cells, but becomes activated in response to oncogenic stress. Here, we show that expression of the histone H3 Lys 27 (H3K27) demethylase JMJD3 is induced upon activation of the RAS–RAF signaling pathway. JMJD3 is recruited to the INK4A–ARF locus and contributes to the transcriptional activation of p16INK4A in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization.

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AP-1 dimers regulate transcription of the p14/p19ARF tumor suppressor gene

Cited by 40 publications

References 58 publications

Synergistic Activation of the Tumor Suppressor, HLJ1, by the Transcription Factors YY1 and Activator Protein 1

Synergistic Activation of the Tumor Suppressor, HLJ1, by the Transcription Factors YY1 and Activator Protein 1

Increased DNA Damage Sensitivity and Apoptosis in Cells Lacking the Snf5/Ini1 Subunit of the SWI/SNF Chromatin Remodeling Complex

The H3K27me3 demethylase JMJD3 contributes to the activation of theINK4A–ARFlocus in response to oncogene- and stress-induced senescence

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