Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells

Nazarenko, Irina; Schäfer, Reinhold; Sers, Christine

doi:10.1242/jcs.000018

Cited by 38 publications

(42 citation statements)

References 79 publications

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“…To address a potential involvement of other PKC isoenzymes, we examined the expression levels and phosphorylation of conventional PKCs α and β; of novel PKCs ε, θ, and δ; and of the atypical PKCι, using the ovarian carcinoma cell line OVCAR-3. We interfered with the PI3K pathway, considered as a major regulator of cell survival and a major oncogenic pathway in epithelial ovarian cancers (28), and with PP2A, defined as a survival phosphatase in several types of human tumors (19,(29)(30)(31). OVCAR-3 cells were either treated with LY294002, an inhibitor of the PI3K pathway, or with okadaic acid, a potent PP2A inhibitor.…”

Section: Resultsmentioning

confidence: 99%

“…As an additional control, we used a function-deficient HRSL3 mutant lacking the NH 2 and COOH termini, and designated here as dNdC. In our previous work, we showed that this mutant is incapable of PP2A interaction and apoptosis induction (19). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Inactivation of total intracellular PP2A by okadaic acid or inhibition of a distinct pool of PP2A through the overexpression of HRSL3 both led to the induction of apoptosis in OVCAR-3 cells. Concomitant inhibition of PKCζ impaired the proapoptotic effect of HRSL3 (19).…”

Section: Introductionmentioning

confidence: 95%

“…In our previous work, we identified the atypical PKCζ as a potential component of a cell death pathway, induced through the HRSL3 tumor suppressor in ovarian cancer (19). HRSL3 (previously named H-REV107-1) is downregulated in ovarian carcinomas and can induce apoptosis upon reexpression (20).…”

Section: Introductionmentioning

confidence: 99%

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Atypical Protein Kinase C ζ Exhibits a Proapoptotic Function in Ovarian Cancer

Nazarenko

Jenny

Keil

et al. 2010

Molecular Cancer Research

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Intracellular signaling governed by serine/threonine kinases comprises the molecular interface between cell surface receptors and the nuclear transcriptional machinery. The protein kinase C (PKC) family members are involved in the control of many signaling processes directing cell proliferation, motility, and survival. Here, we examined a role of different PKC isoenzymes in protein phosphatase 2A (PP2A) and HRSL3 tumor suppressordependent cell death induction in the ovarian carcinoma cell line OVCAR-3. Phosphorylation and activity of PKC isoenzymes were measured in response to PP2A or phosphoinositide 3-kinase inhibition or HRSL3 overexpression. These experiments indicated a regulation of PKCθ, ε, ζ, and ι through PP2A and/or HRSL3, but not of PKCα and β. Using isoform-specific peptide inhibitors and overexpression approaches, we verified a contribution to PP2A-and HRLS3-dependent apoptosis only for PKCζ, suggesting a proapoptotic function of this kinase. We observed a significant proportion of human ovarian carcinomas expressing high levels of PKCζ, which correlated with poor prognosis. Primary ovarian carcinoma cells isolated from patients also responded to okadaic acid treatment with increased phosphorylation of PKCζ and apoptosis induction. Thus, our data indicate a contribution of PKCζ in survival control in ovarian carcinoma cells and suggest that upregulation or activation of tyrosine kinase receptors in this tumor might impinge onto apoptosis control through the negative regulation of the atypical PKCζ. Mol Cancer Res; 8(6); 919-34. ©2010 AACR.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Atypical Protein Kinase C ζ Exhibits a Proapoptotic Function in Ovarian Cancer

Nazarenko

Jenny

Keil

et al. 2010

Molecular Cancer Research

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“…Pla2g16 is also called H-REV-107, HRASLS3 (Ha-RAS like suppressor 3), and AdPLA (adipose specific PLA2) (19)(20)(21) and was first identified as a class II tumor suppressor, because it suppressed Ras-mediated transformation in cultured cells, and its overexpression led to proliferation inhibition and apoptosis (19,(22)(23)(24). However, Pla2g16 was also labeled an oncogene because it increases proliferation of nonsmall-cell lung cancer cells and its overexpression correlates with a poor prognosis (25).…”

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confidence: 99%

Pla2g16 phospholipase mediates gain-of-function activities of mutant p53

Xiong¹,

Tu²,

Kollareddy

et al. 2014

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

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p53 R172H/+ mice inherit a p53 mutation found in Li-Fraumeni syndrome and develop metastatic tumors at much higher frequency than p53 +/− mice. To explore the mutant p53 metastatic phenotype, we used expression arrays to compare primary osteosarcomas from p53 R172H/+ mice with metastasis to osteosarcomas from p53 +/− mice lacking metastasis. For this study, 213 genes were differentially expressed with a P value <0.05. Of particular interest, Pla2g16, which encodes a phospholipase that catalyzes phosphatidic acid into lysophosphatidic acid and free fatty acid (both implicated in metastasis), was increased in p53 R172H/+ osteosarcomas. Functional analyses showed that Pla2g16 knockdown decreased migration and invasion in mutant p53-expressing cells, and vice versa: overexpression of Pla2g16 increased the invasion of p53-null cells. Furthermore, Pla2g16 levels were increased upon expression of mutant p53 in both mouse and human osteosarcoma cell lines, indicating that Pla2g16 is a downstream target of the mutant p53 protein. ChIP analysis revealed that several mutant p53 proteins bind the Pla2g16 promoter at E26 transformationspecific (ETS) binding motifs and knockdown of ETS2 suppressed mutant p53 induction of Pla2g16. Thus, our study identifies a phospholipase as a transcriptional target of mutant p53 that is required for metastasis. mammary tumor | fatty acid metabolism T he p53 tumor suppressor pathway is inactivated in ∼50% of human cancers (http://p53.iarc.fr). Missense mutations in particular account for 80% of p53 alterations, suggesting that mutant p53 proteins provide additional advantages for tumor cell growth (1). Li-Fraumeni syndrome patients with p53 missense mutations have a higher cancer incidence and an earlier age of tumor onset than individuals with truncating or splicing mutations (2). p53 knockin mice show a gain-of-function (GOF) phenotype in vivo, with high metastatic capacity compared with mice inheriting a p53-null allele (3, 4). GOF activities of mutant p53 are mediated by suppression of the p53 family members, p63 and p73 (3-6). Other mechanisms of mutant p53 GOF include mutant-p53 complexes with Smad that fuel TGF-β-induced metastasis (7) and integrin recycling (8). Additionally, mutant p53 interacts with the vitamin D receptor and converts vitamin D into an antiapoptotic agent (9-14). More recently, mutant p53 was reported to form transcriptional complexes on promoters of genes encoding several enzymes of the Mevalonate pathway, which increases metastasis of breast cancer cells (9). These data suggest multiple pathways contribute to the GOF phenotypes of cells with mutant p53. Although mutant p53 lacks sequencespecific DNA binding activity, its interaction with other transcriptional factors or the components of basic transcriptional machinery allow it to modulate gene expression (15). ChIP-onchip and ChIP-sequencing techniques show that mutant p53 affects transcription of many genes (9, 13, 16, 17).In this study, expression array analyses identified gene differences between p53 R172H/+ m...

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Cloning and functional characterization of the HRASLS2 gene

Shyu¹,

Hsieh²,

Tsai³

et al. 2007

Amino Acids

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The HRAS-like suppressor 2 (HRASLS2) gene belongs to the H-REV107 gene family involved in the regulation of cell growth and differentiation. HRASLS2 is expressed at high levels in normal tissues of the small intestine, kidney, and trachea. We cloned HRASLS2 cDNA from human SW480 colon cancer cells. Most wild-type, and some N- and C-terminal truncated HRASLS2 (HRASLS2DeltaNDeltaC) were expressed as a granular pattern located at perinuclear region in HtTA cervical cancer cells, while truncation at the C-terminus only (HRASLS2DeltaC) resulted in a diffuse pattern. Wild-type HRASLS2 significantly suppressed colony formation of HeLa and HCT116 cells. HRASLS2DeltaNDeltaC significantly inhibited colony formation of HCT116 cells, but HRASLS2DeltaC did not affect cell growth. HRASLS2 suppressed the RAS-GTP levels and total RAS protein by 44% and 25%, respectively in HtTA cells; however, the suppression was not observed in truncated HRASLS2 variants. In conclusion, the HRASLS2 protein suppressed growth and RAS activities of cancer cells, and the C-terminal hydrophobic domain appeared to be indispensable for both activities.

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Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells

Cited by 38 publications

References 79 publications

Atypical Protein Kinase C ζ Exhibits a Proapoptotic Function in Ovarian Cancer

Atypical Protein Kinase C ζ Exhibits a Proapoptotic Function in Ovarian Cancer

Pla2g16 phospholipase mediates gain-of-function activities of mutant p53

Cloning and functional characterization of the HRASLS2 gene

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