Maf and Jun Nuclear Oncoproteins Share Downstream Target Genes for Inducing Cell Transformation

Kataoka, Kohsuke; Shioda, Shigeo; Yoshitomo-Nakagawa, Kiyomi; Handa, Hiroshi; Nishizawa, Makoto

doi:10.1074/jbc.m102234200

Cited by 23 publications

(15 citation statements)

References 30 publications

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“…30). A previous study suggested that the cis-regulatory sequence recognized by Jun homodimer is necessary for Maf-induced transformation (31). Although there are several possibilities, we favor the interpretation that the MARE sequence shared by AP-1 (Jun/Fos) and Maf, which should behave as a dual MARE, is involved in Maf-induced transformation.…”

Section: Discussionmentioning

confidence: 71%

Molecular Basis Distinguishing the DNA Binding Profile of Nrf2-Maf Heterodimer from That of Maf Homodimer

Kimura

Yamamoto

Zhang

et al. 2007

Journal of Biological Chemistry

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Nrf2-small Maf heterodimer activates the transcription of many cytoprotective genes through the antioxidant response element and serves as a key factor in xenobiotic and oxidative stress responses. Our surface plasmon resonance-microarray binding analysis revealed that both Nrf2-MafG heterodimer and MafG homodimer bind to the consensus Maf recognition element with high affinity but bind differentially to the suboptimal binding sequences degenerated from the consensus. We examined the molecular basis distinguishing the binding profile of Nrf2-MafG heterodimer from that of MafG homodimer and found that the Ala-502 residue in the basic region of Nrf2 is a critical determinant of its binding specificity. In Maf proteins, a tyrosine resides in the position corresponding to Ala-502 in Nrf2. We prepared a mutant Nrf2 molecule in which Ala-502 was replaced with tyrosine. In surface plasmon resonance-microarray analysis, heterodimer of Nrf2(A502Y) and MafG displayed a binding specificity similar to that of MafG homodimer. The target genes activated by mutant Nrf2(A502Y)-small Maf heterodimer were largely different, albeit with some overlap, from those activated by wild-type Nrf2-small Maf, indicating that the array of target genes regulated by Nrf2-small Maf heterodimer differs substantially from that regulated by Maf homodimer in vivo. These results suggest that the distinct DNA binding profile of Nrf2-Maf heterodimer is biologically significant for Nrf2 to function as a key regulator of cytoprotective genes. Our contention is supported that the differential DNA binding specificity between Maf homodimers and Nrf2-Maf heterodimers establishes the differential gene regulation by these dimer-forming transcription factors.

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Section: Discussionmentioning

confidence: 71%

Molecular Basis Distinguishing the DNA Binding Profile of Nrf2-Maf Heterodimer from That of Maf Homodimer

Kimura

Yamamoto

Zhang

et al. 2007

Journal of Biological Chemistry

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“…Cadherin 11 expression has not been reported in mesotheliomas. The v-MAF oncogene is a homodimeric protein with a basic leucine zipper structure at its COOH terminus, which binds to palindromic DNA sequences termed MAREs and is able to induce cell transformation (48). Its expression has not been previously shown in mesothelioma.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Signatures Differentiate Ovarian/Peritoneal Serous Carcinoma from Diffuse Malignant Peritoneal Mesothelioma

Davidson

Zhen²,

Kleinberg

et al. 2006

Clinical Cancer Research

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Purpose: Ovarian/primary peritoneal serous carcinoma (OC/PPC) and diffuse peritoneal malignant mesothelioma (DMPM) are highly aggressive tumors that are closely related morphologically and histogenetically. It remains unclear whether both tumors are molecularly distinct neoplasms. The current study compared global gene expression patterns in OC/PPC and DMPM. Experimental Design: Ten OC/PPC and five DMPM effusions were analyzed for gene expression profiles using the Affymetrix U133 Plus 2 arrays and the dCHIP analysis program. Differentially expressed candidate genes were validated using quantitative real-time PCR and immunohistochemistry. Results: Unsupervised hierarchical clustering using all 54,675 genes in the array classified the samples into two groups: DMPM specimens versus OC/PPC specimens. A total of 189 genes that were differentially expressed in these two groups were selected based on statistical significance. Genes overexpressed in DMPM (n = 68) included calretinin, vitronectin, claudin 15, a 4 laminin, hyaluronan synthase 1, cadherin 11, RAB7, v-maf, and the epidermal growth factor^containing fibulin-like extracellular matrix protein 1. Genes overexpressed in OC/PPC (n = 121) included insulin-like growth factor II (IGF-II); IGF-II binding protein 3; cyclin E1; folate receptors 1 and 3; RAB25; MUC4; endothelin-1; CD24; kallikreins 6, 7, and 8; claudins 3, 4, and 6; Notch3; and MMP-7. Quantitative real-time PCR validated the differential expression of 13 genes, and immunohistochemistry confirmed the differences for four gene products. Conclusions: Expression profiling separates OC/PPC from DMPM and identifies a number of genes that are differentially expressed in these tumors. The molecular signatures unique to OC/PPC and DMPM should provide a molecular basis to study both tumors and new potential markers for facilitating their differential diagnosis.Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive cancer that originates from the native mesothelial cells of the peritoneal cavity. DMPM is less common than its pleural counterpart (9:1 ratio), differs in its gender predilection (roughly similar incidence in women and men), and has a weaker etiologic link to asbestos exposure (1, 2). The prognosis of DMPM patients has been extremely poor in earlier series, with median survival of 10 to 12 months (2). However, recent studies have shown improved survival (26-92 months) when DMPM patients are treated aggressively with combined debulking and preheated i.p. chemotherapy consisting of cisplatin, doxorubicin, and paclitaxel as major agents (2 -4). Recently, a response rate of 25% was achieved following pemetrexed treatment (5). The majority of DMPM are of the epithelioid type (6).Ovarian cancer (OC) is the most lethal gynecologic malignancy in the Western world and the fourth most frequent cause of cancer-related death in women (7). As DMPM, OC and the closely related and morphologically indistinguishable primary peritoneal carcinoma (PPC) are thought to develop from the peritoneal mesot...

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“…We constructed several fusion proteins that include the DNA-binding domain of MafA and the hormone-binding domain of the human ER (Kumar et al, 1986). We have found that v-Maf and MafA with the zipper domain replaced by the yeast GCN4 retain transforming ability (Kataoka et al, 2001;Nishizawa, 2002, unpublished observation). We used the MafA-GCN4 chimera for the ER fusions because the GCN4 zipper domain only homodimerizes, eliminating potentially complicating interactions with other bZip proteins.…”

Section: Construction Of An Inducible Cell Transformation Systemmentioning

confidence: 99%

MafA has strong cell transforming ability but is a weak transactivator

2003

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The maf oncogene of the avian oncogenic retrovirus AS42 encodes a nuclear bZip protein, v-Maf, that recognizes sequences related to the AP-1 target site. The corresponding cellular protein, c-Maf belongs to a family of related bZip proteins together with MafA and MafB. In this paper, we compare the transactivation and cell transforming abilities of MafA and MafB along with two forms of the c-Maf protein. These proteins induce cellular transformation when expressed in chicken embryo fibroblasts. In reporter assays, MafA is a much less effective transactivator than the other Maf proteins, but unexpectedly shows the strongest activity in cell transformation. Chimeras of MafA and MafB correlate the strong cell transforming ability of MafA with its DNA-binding domain. The DNA-binding domain of MafA is also correlated with weak transactivation. Additional mutagenesis experiments show that transactivation and transformation by MafA are also controlled by phosphorylation of two conserved serine residues in the transactivation domain. Finally, we constructed MafAestrogen receptor fusion molecules that show tightly hormone-dependent cell transforming ability. These regulatable constructs permit a kinetic characterization of target gene responses and facilitate discrimination between direct and indirect targets.

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Maf and Jun Nuclear Oncoproteins Share Downstream Target Genes for Inducing Cell Transformation

Cited by 23 publications

References 30 publications

Molecular Basis Distinguishing the DNA Binding Profile of Nrf2-Maf Heterodimer from That of Maf Homodimer

Molecular Basis Distinguishing the DNA Binding Profile of Nrf2-Maf Heterodimer from That of Maf Homodimer

Gene Expression Signatures Differentiate Ovarian/Peritoneal Serous Carcinoma from Diffuse Malignant Peritoneal Mesothelioma

MafA has strong cell transforming ability but is a weak transactivator

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