14-3-3ζ Cooperates with ErbB2 to Promote Ductal Carcinoma In Situ Progression to Invasive Breast Cancer by Inducing Epithelial-Mesenchymal Transition

Lü, Jing; Guo, Hua; Treekitkarnmongkol, Warapen; Li, Ping; Zhang, Jian; Shu, Bin; Chen, Ling; Zhou, Xiaoyan; Chen, Tongzhen; Chiao, Paul J.; Feng, Xin‐Hua; Seewaldt, Victoria L.; Muller, William J.; Şahin, Ayşegül; Hung, Mien‐Chie; Yu, Dihua

doi:10.1016/j.ccr.2009.08.010

Cited by 178 publications

(195 citation statements)

References 41 publications

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“…Another possibility would be that the inactivation of p21 by 14-3-3 might be cell-specific. 14-3-3 has been shown to play an oncogenic role in breast cancer development and progression (47). Consistent with this role, this 14-3-3 isoform does not appear to induce the level of endogenous p21 significantly (Fig.…”

Section: Discussionsupporting

confidence: 55%

14-3-3γ Inhibition of MDMX-mediated p21 Turnover Independent of p53

Lee

2011

Journal of Biological Chemistry

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The stability of p21, a cyclin-dependent kinase inhibitor, is highly regulated by various protein molecules through the cell cycle and in response to extracellular signals. One of the p21 regulators is MDMX, which can directly bind to p21 and mediate its proteasomal degradation in an ubiquitination-independent fashion. The fact that 14-3-3␥ binds to the MDMX domain adjacent to p21 binding suggests that this 14-3-3␥ may affect MDMX-mediated p21 proteasomal turnover. Indeed, we found that overexpression of 14-3-3␥ increased the level of both endogenous and exogenous p21 in p53-null cells by extending its half-life, leading to p21-dependent G1 arrest. Also, 14-3-3␥ excluded p21 from binding to MDMX in a dose-dependent manner as determined by co-immunroprecipitation in vitro using purified proteins and in cells. In response to DNA damage, the level of the 14-3-3␥-MDMX complex increased whereas that of the MDMX-p21 complex declined as detected by co-immunoprecipitation assays, leading to the induction of p21 in p53-null cells. Knockdown of 14-3-3␥ inversely alleviated the induction of p21 levels by DNA damage. Hence, our study as presented here unravels a new role for 14-3-3␥ in protecting p21 from MDMX-mediated proteasomal turnover, which may partially account for DNA damage-induced elevation of p21 levels independent of p53.

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Section: Discussionsupporting

confidence: 55%

14-3-3γ Inhibition of MDMX-mediated p21 Turnover Independent of p53

Lee

2011

Journal of Biological Chemistry

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“…14-3-3σ expression is inhibited in premalignant and malignant cells (5), and loss of 14-3-3σ results in polyploidy and failure to maintain G2/M cell-cycle arrest after DNA damage through cytoplasmic sequestration of CDC2/cyclin B1 (6, 7). 14-3-3ζ expression is up-regulated in various cancers (8), and it induces epithelial-mesenchymal transition by activation of TGF-β/Smads and inhibits apoptosis in anoikic cells, thereby potentiating tumor invasion and metastasis (9,10). Although these observations demonstrate functional roles for altered expression of 14-3-3 in tumorigenesis, there have heretofore been no reported instances of genomically aberrant 14-3-3 oncogenes.…”

mentioning

confidence: 66%

14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma

Lee

Mariño-Enríquez

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

240

230

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14-3-3 proteins are ubiquitously expressed regulators of various cellular functions, including proliferation, metabolism, and differentiation, and altered 14-3-3 expression is associated with development and progression of cancer. We report a transforming 14-3-3 oncoprotein, which we identified through conventional cytogenetics and whole-transcriptome sequencing analysis as a highly recurrent genetic mechanism in a clinically aggressive form of uterine sarcoma: high-grade endometrial stromal sarcoma (ESS). The 14-3-3 oncoprotein results from a t (10;17) genomic rearrangement, leading to fusion between 14-3-3ε (YWHAE) and either of two nearly identical FAM22 family members (FAM22A or FAM22B). Expression of YWHAE–FAM22 fusion oncoproteins was demonstrated by immunoblot in t (10;17)-bearing frozen tumor and cell line samples. YWHAE–FAM22 fusion gene knockdowns were performed with shRNAs and siRNAs targeting various FAM22A exons in an t (10;17)-bearing ESS cell line (ESS1): Fusion protein expression was inhibited, with corresponding reduction in cell growth and migration. YWHAE–FAM22 maintains a structurally and functionally intact 14-3-3ε (YWHAE) protein-binding domain, which is directed to the nucleus by a FAM22 nuclear localization sequence. In contrast to classic ESS, harboring JAZF1 genetic fusions, YWHAE–FAM22 ESS display high-grade histologic features, a distinct gene-expression profile, and a more aggressive clinical course. Fluorescence in situ hybridization analysis demonstrated absolute specificity of YWHAE–FAM22A/B genetic rearrangement for high-grade ESS, with no fusions detected in other uterine and nonuterine mesenchymal tumors (55 tumor types, n = 827). These discoveries reveal diagnostically and therapeutically relevant models for characterizing aberrant 14-3-3 oncogenic functions.

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“…14-3-3 proteins promote cell survival through their interactions with key signaling proteins (such as epithelial growth factor receptor, Raf-1, and Akt) and BH3 domain-containing proteins (Bad, Bcl-2, Bax, and Bcl-xL; refs. [22][23][24][25][26][27][28]. Suppression of apoptosis is effected through interactions with the Bcl-2 antagonist of cell death (Bad), Bcl-2-interacting mediator of cell death (Bim), and Bcl-2-associated x protein (Bax), which are core components of the mitochondrial apoptotic machinery, and through interactions with proteins that transmit apoptotic signals, including the stressresponsive kinase ASK1 (MEKK5) and the forkhead box O1 (FOXO) transcription factors (24,27).…”

Section: Introductionmentioning

confidence: 99%

Small Interfering RNA Targeting 14-3-3ζ Increases Efficacy of Chemotherapeutic Agents in Head and Neck Cancer Cells

Matta

DeSouza

Ralhan

et al. 2010

Molecular Cancer Therapeutics

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Patients diagnosed in advanced stages of head and neck squamous cell carcinoma often show limited response to chemotherapeutic agents. Recently, we reported the overexpression of 14-3-3ζ protein in head and neck premalignant and cancer tissues using liquid chromatography-tandem mass spectrometry with isotopic labeling and revealed its significance as a prognostic marker using immunohistochemical analysis. In this study, we determined the potential of 14-3-3ζ as a therapeutic target for head and neck cancer. Small interfering RNA (siRNA) targeting 14-3-3ζ was used to downregulate its expression in head and neck cancer cells in culture. Cell cycle analysis showed that head and neck cancer cells transfected with siRNA targeting 14-3-3ζ showed G 2 -M arrest. These siRNA transfectants also showed increased cell death on treatment with any one of the following chemotherapeutic agents: cisplatin, 5-fluorouracil, paclitaxel, or doxorubicin in comparison with the no transfection controls. Flow cytometric analysis using propidium iodide staining showed increased sub-G 0 fraction in siRNA-transfected cells treated with any of these chemotherapeutic agents, suggesting cell death; in addition, Annexin V staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay revealed increased apoptosis. Taken together, our results strongly showed that downregulation of 14-3-3ζ expression may serve to improve the sensitivity of head and neck cancer cells to chemotherapeutic agents. Mol Cancer Ther; 9(10); 2676-88. ©2010 AACR.

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14-3-3ζ Cooperates with ErbB2 to Promote Ductal Carcinoma In Situ Progression to Invasive Breast Cancer by Inducing Epithelial-Mesenchymal Transition

Cited by 178 publications

References 41 publications

14-3-3γ Inhibition of MDMX-mediated p21 Turnover Independent of p53

14-3-3γ Inhibition of MDMX-mediated p21 Turnover Independent of p53

14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma

Small Interfering RNA Targeting 14-3-3ζ Increases Efficacy of Chemotherapeutic Agents in Head and Neck Cancer Cells

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