Inefficient proteasomal‐degradation pathway stabilizes AP‐2α and activates HER‐2/<i>neu</i> gene in breast cancer

Li, Min; Wang, Yingqun; Hung, Mien‐Chie; Kannan, Perry

doi:10.1002/ijc.21426

Cited by 26 publications

(26 citation statements)

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“…The central basic domain and the helix-span-helix motif were essential for DNA binding and dimerization (28). In our experiment, CK2 phosphorylates the position of S429, and increase the protein stability of AP-2α, which consistent with the reporter that the C-terminal 90 amino acids of AP-2α are responsible for protein stability (29). The interaction domain of AP-2α with CK2β located in the N-terminal moiety, which could explain our results that the transcriptional activity of the mutant AP-2α (S429A) was partially activated by CK2, maybe the mutation didn't disrupt the interaction (data not shown) between them, the CK2 upregulates AP-2α by promoting its protein stability.…”

Section: Discussionsupporting

confidence: 86%

CK2 phosphorylates AP-2α and increases its transcriptional activity

Ren

Xian²,

He³

et al. 2011

BMB Reports

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Transcription factor AP-2α involves in the process of mammalian embryonic development and tumorigenesis. Many studies have shown that AP-2α functions in association with other interacting proteins. In a two-hybrid screening, the regulatory subunit β of protein casein kinase 2 (CK2β) was identified as an interacting protein of AP-2α; we confirmed this interaction using in-vitro GST pull-down and in-vivo co-immunoprecipitation assays; in an endogenous co-immunoprecipitation experiment, we further found the catalytic subunit α of protein casein kinase 2 (CK2α) also exists in the complex. Phosphorylation analysis revealed that AP-2α was phosphorylated by CK2 kinase majorly at the site of Ser429, and such phosphorylation could be blocked by CK2 specific inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) in a dose-dependent manner. Luciferase assays demonstrated that both CK2α and CK2β enhanced the transcription activity of AP-2α; moreover, CK2β increased the stability of AP-2α. Our data suggest a novel cellular function of CK-2 as a transcriptional co-activator of AP-2α. [BMB reports 2011; 44(7): 490-495]

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Section: Discussionsupporting

confidence: 86%

CK2 phosphorylates AP-2α and increases its transcriptional activity

Ren

Xian²,

He³

et al. 2011

BMB Reports

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“…We used the breast cancer cell line MDA-MB-453 cell line, which carries elevated levels of AP-2␣ (Fig. 7, C and D, lane 1) as previously reported (39). We found that treatment of MDA-MB-453 cells with staurosporine or okadaic acid resulted in apoptosis induction, as evidenced by an increase in the percentage of cells with less than 2N content of DNA (Fig.…”

Section: Ap-2␣ Induces Apoptosis By Transcriptionally Down-regulatingmentioning

confidence: 55%

“…Although the endogenous level of AP-2␣ in most cell lines has been found to be low, increased levels have been reported in certain breast cancer cells (39). Because AP-2␣ is a potent growth inhibitory protein, the high levels seen in these cells might reflect a functionally inactive state.…”

Section: Discussionmentioning

confidence: 99%

“…To demonstrate the physiological relevance of apoptosis induction by AP-2␣, we analyzed apoptosis induction by AP-2␣ upon chemotherapy treatment or 5aza2dC treatment. Upon treatment of SW480 cells with adriamycin or cisplatin resulted in increase in endogenous AP-2␣ ( Okadaic Acid or Staurosporine Treatment Induces AP-2␣-dependent Apoptosis in Breast Cancer Cells-An inefficient proteosomal degradation pathway has been found to be responsible for high levels of AP-2␣ in certain breast cancer-derived cells (39). We hypothesized that the growth inhibitory functions of AP-2␣ is inhibited in these cells by survival signaling, inhibition of which might restore its functions.…”

Section: Ap-2␣ Induces Apoptosis By Transcriptionally Down-regulatingmentioning

confidence: 99%

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Apoptosis Induction by Activator Protein 2α Involves Transcriptional Repression of Bcl-2

Wajapeyee¹,

Britto

Ravishankar

et al. 2006

Journal of Biological Chemistry

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Activator protein 2␣ (AP-2␣) 3 is a sequence-specific DNA binding transcription factor that is required for normal growth and morphogenesis (1-3). AP-2␣ has a conserved C-terminal DNA binding motif with an integral helix-span-helix homodimerization motif and a less-conserved proline and aromatic amino acid-rich helix transactivation domain near the N terminus and binds to a consensus DNA sequence, 5Ј-GCCNNNGGC-3Ј (4 -8). AP-2␣ has been shown to regulate many genes involved in variety of biological functions (9).Several lines of evidences indicate that AP-2␣ may act as a tumor suppressor gene. AP-2␣ gene is located in chromosome position 6p22, a region of frequent loss of heterozygosity in breast and other cancers (10). Diminished AP-2␣ function has been correlated with N-Ras oncogene-mediated transformation (11). The functions of AP-2␣ have been shown to be regulated by SV40 T antigen and adenovirus E1A oncoproteins (1, 12). In addition, reduced or loss of AP-2␣ expression has been reported in human cancers of breast, ovary, colon, skin, brain, and prostate (13)(14)(15)(16)(17)(18)(19)(20). In good correlation, expression of dominant negative mutant AP-2␣ resulted in increased invasiveness and tumorigenicity (21).Overexpression of AP-2␣ by transient transfection into cultured cells has been shown to induce p21 WAF1/CIP1 and inhibit cellular DNA synthesis and colony formation (22). Significant correlation between AP-2␣ expression and p21 WAF1/CIP1 has been observed in breast cancer, colorectal cancer, and malignant melanoma (15,18,23). The growth inhibitory activity of AP-2␣ has also been shown to be mediated through direct interaction with p53 (24). Results from our laboratory suggest that adenovirus-mediated overexpression of AP-2␣ inhibits growth of cancer cells by inhibiting cellular DNA synthesis and inducing apoptosis (25). Furthermore, our recent work establishes that AP-2␣ is induced in cancer cells upon treatment with chemotherapeutic drugs, which contributes to chemosensitivity because the simultaneous inhibition of AP-2␣ by siRNA increases the chemoresistance. In addition, the re-expression of epigenetically silenced AP-2␣ in breast cancer resulted in enhanced chemosensitivity and loss of tumorigenicity upon chemotherapy in an AP-2␣-dependent manner (26). These results point out the importance of apoptosis induction by AP-2␣ for its functions, particularly the role in chemosensitivity.The molecular mechanism by which AP-2␣ induces apoptosis is not known. In the present study we have analyzed the pathways and various molecules involved in AP-2␣-induced apoptosis. We found that AP-2␣-induced apoptosis requires primarily the mitochondrial pathway involving a bax/cytochrome c/Apaf1/caspase 9-dependent mechanism. We also found that AP-2␣ binds to the Bcl-2 promoter leading to its transcriptional down-regulation and is essential for the apoptosis induction by AP-2␣. In addition, we provide evidence that the overexpressed AP-2␣ (perhaps functionally inactive) in certain breast cancer cells can be made functio...

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“…Previously it has been suggested that TFAP2A levels may be regulated in breast epithelial cells via alterations in the efficiency of degradation via the proteasome, particularly between normal and tumor cells. 22 Alternatively, prost-transcriptional regulation of TFAP2A may involve miRNAs since targeted inactivation of Dicer in mouse expression of either p53 or TFAP2A (see Fig. 3, lanes 2 and 4) further demonstrating that TFAP2A is able to induce CDKN1A expression even in the absence of p53.…”

Section: Resultsmentioning

confidence: 95%