Dual association by TFAP2A during activation of the p21cip/CDKN1A promoter

Scibetta, Angelo G.; Wong, Ping-Pui; Chan, KaYi V.; Canosa, Monica; Hurst, Helen C.

doi:10.4161/cc.9.22.13746

Cited by 20 publications

(23 citation statements)

References 24 publications

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“…We have previously identified an AP-2 DNA binding site (GCCCCGGGG) at Ϫ111/Ϫ103 in the CDKN1A promoter (27). In contrast, there is no consensus Myc binding site within the proximal promoter, and it is thought that Myc is recruited to the locus by "piggy-backing" on other factors, such as Miz-1 or Sp1, that bind to sites within 100 bp of the CDKN1A TSS (17,29).…”

Section: Resultsmentioning

confidence: 99%

“…CDKN1A luciferase constructs mutated to abolish AP-2 binding (mut4 and mut5) (27). Mutation of the AP-2 binding site clearly abrogated repression by TFAP2C alone and with KDM5B (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The pcDNA3.1-based TFAP2C and KDM5B expression plasmids, the pGL-3-CDKN1A luciferase reporter, and pGL-3-Mut4/Mut5 constructs have been previously described (26,27). The fusion protein GFP-TFAP2C was generated by cloning the TFAP2C cDNA sequence in frame into the pEGFP-C1 vector (Clontech).…”

Section: Methodsmentioning

confidence: 99%

“…Of particular interest is the regulation of the universal cell cycle inhibitor p21 cip (CDKN1A), which can be activated through p53-dependent and -independent pathways to mediate cell cycle arrest (1). AP-2 factors bind a specific sequence in the proximal region of the promoter, and while TFAP2A positively regulates CDKN1A expression (27,41), TFAP2C has been shown to repress its expression in breast cancer cells (36). These opposing activities at the CDKN1A locus may contribute to the contrasting phenotypes associated with tumors expressing these two AP-2 factors.…”

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confidence: 99%

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Histone Demethylase KDM5B Collaborates with TFAP2C and Myc To Repress the Cell Cycle Inhibitor p21^cip (CDKN1A)

Wong

Miranda

Chan

et al. 2012

Molecular and Cellular Biology

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The TFAP2C transcription factor has been shown to downregulate transcription of the universal cell cycle inhibitor p21 cip (CDKN1A). In examining the mechanism of TFAP2C-mediated repression, we have identified a ternary complex at the proximal promoter containing TFAP2C, the oncoprotein Myc, and the trimethylated lysine 4 of histone H3 (H3K4me3) demethylase, KDM5B. We demonstrated that while TFAP2C and Myc can downregulate the CDKN1A promoter independently, KDM5B acts as a corepressor dependent on the other two proteins. All three factors collaborate for optimal CDKN1A repression, which requires the AP-2 binding site at ؊111/؊103 and KDM5B demethylase activity. Silencing of TFAP2C-KDM5B-Myc led to increased H3K4me3 at the endogenous promoter and full induction of CDKN1A expression. Coimmunoprecipitation assays showed that TFAP2C and Myc associate with distinct domains of KDM5B and the TFAP2C C-terminal 270 amino acids (aa) are required for Myc and KDM5B interaction. Overexpression of all three proteins resulted in forced S-phase entry and attenuation of checkpoint activation, even in the presence of chemotherapy drugs. Since each protein has been linked to poor prognosis in breast cancer, our findings suggest that the TFAP2C-Myc-KDM5B complex promotes cell cycle progression via direct CDKN1A repression, thereby contributing to tumorigenesis and therapy failure.

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Section: Resultsmentioning

confidence: 99%

“…CDKN1A luciferase constructs mutated to abolish AP-2 binding (mut4 and mut5) (27). Mutation of the AP-2 binding site clearly abrogated repression by TFAP2C alone and with KDM5B (Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Histone Demethylase KDM5B Collaborates with TFAP2C and Myc To Repress the Cell Cycle Inhibitor p21^cip (CDKN1A)

Wong

Miranda

Chan

et al. 2012

Molecular and Cellular Biology

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“…TFAP2A functions as a tumor suppressor in several solid tumors including breast cancer (43,44). Overexpression of Tfap2a and Tfap2c mimics the mammary phenotype of RANK null mice (5,45,46).…”

Section: Discussionmentioning

confidence: 99%

RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation

et al. 2016

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RANK expression is associated with poor prognosis in breast cancer even though its therapeutic potential remains unknown. RANKL and its receptor RANK are downstream effectors of the progesterone signaling pathway. However, RANK expression is enriched in hormone receptor negative adenocarcinomas, suggesting additional roles for RANK signaling beyond its hormonedependent function. Here, to explore the role of RANK signaling once tumors have developed, we use the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT), which mimics RANK and RANKL expression patterns seen in human breast adenocarcinomas. Complementary genetic and pharmacologic approaches demonstrate that therapeutic inhibition of RANK signaling drastically reduces the cancer stem cell pool, decreases tumor and metastasis initiation, and enhances sensitivity to chemotherapy. Mechanistically, genome-wide expression analyses show that anti-RANKL therapy promotes lactogenic differentiation of tumor cells. Moreover, RANK signaling in tumor cells negatively regulates the expression of Ap2 transcription factors, and enhances the Wnt agonist Rspo1 and the Sca1-population, enriched in tumor-initiating cells. In addition, we found that expression of TFAP2B and the RANK inhibitor, OPG, in human breast cancer correlate and are associated with relapse-free tumors. These results support the use of RANKL inhibitors to reduce recurrence and metastasis in breast cancer patients based on its ability to induce tumor cell differentiation. Cancer Res; 76(19); 5857-69. Ó2016 AACR.

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Shared molecular networks in orofacial and neural tube development

Kousa

Mansour

Seada

et al. 2017

Birth Defects Research

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Dual association by TFAP2A during activation of the p21cip/CDKN1A promoter

Cited by 20 publications

References 24 publications

Histone Demethylase KDM5B Collaborates with TFAP2C and Myc To Repress the Cell Cycle Inhibitor p21^cip (CDKN1A)

Histone Demethylase KDM5B Collaborates with TFAP2C and Myc To Repress the Cell Cycle Inhibitor p21^cip (CDKN1A)

RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation

Shared molecular networks in orofacial and neural tube development

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Dual association by TFAP2A during activation of the p21cip/CDKN1A promoter

Cited by 20 publications

References 24 publications

Histone Demethylase KDM5B Collaborates with TFAP2C and Myc To Repress the Cell Cycle Inhibitor p21cip (CDKN1A)

Histone Demethylase KDM5B Collaborates with TFAP2C and Myc To Repress the Cell Cycle Inhibitor p21cip (CDKN1A)

RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation

Shared molecular networks in orofacial and neural tube development

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Product

Resources

About

Histone Demethylase KDM5B Collaborates with TFAP2C and Myc To Repress the Cell Cycle Inhibitor p21^cip (CDKN1A)

Histone Demethylase KDM5B Collaborates with TFAP2C and Myc To Repress the Cell Cycle Inhibitor p21^cip (CDKN1A)