Marina Wolfson

Publications of Marina Wolfson

• Enhanced genetic instability and dasatinib sensitivity in mammary tumor cells lacking NEDD9.

  Authors: Mahendra K Singh, Eugene Izumchenko, Andres J Klein-Szanto, Brian L Egleston, Marina Wolfson, Erica A Golemis

  Cancer research. 10/2010; 70(21):8907-16.

  Elevated expression of the NEDD9/HEF1/Cas-L scaffolding protein promotes tumor cell invasion and metastasis in multiple cancer cell types. Conversely, generation of mammary tumors in the mouseElevated expression of the NEDD9/HEF1/Cas-L scaffolding protein promotes tumor cell invasion and metastasis in multiple cancer cell types. Conversely, generation of mammary tumors in the mouse mammary tumor virus (MMTV)-polyoma virus middle T (PyVT) genetic model is delayed by a Nedd9(-/-) genotype. These activities arise from the role of NEDD9 in assembling complexes and supporting activity of cancer signaling proteins, including FAK, Src, Shc, and AKT, and would support evaluation of NEDD9 expression as an unambiguous biomarker for tumor aggressiveness. However, we here show that despite the initial delay in tumor growth, cells derived from MMTV-PyVT;Nedd9(-/-) tumors are characteristically hyperaggressive versus MMTV-PyVT;Nedd9(+/+) cells in anchorage-independent growth, in growth on three-dimensional matrix produced by tumor-associated fibroblasts, and in formation of tumors after mammary orthotopic reinjection and of lung metastases after tail vein injection. This reversal suggests the specific selection of MMTV-PyVT;Nedd9(-/-) cells for growth in an in vivo microenvironment. Indeed, MMTV-PyVT;Nedd9(-/-) cells have increased cell cycle, centrosomal, and mitotic defects, phenotypes compatible with the increased selection of these cells for aggressive growth. Intriguingly, in spite of their aggressive phenotype, MMTV-PyVT;Nedd9(-/-) cells persistently have low levels of Src activation and are hypersensitive to the Src kinase inhibitor dasatinib. These studies identify NEDD9 as a complex modulator of different aspects of mammary tumor growth.

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• MicroRNA-regulated protein-protein interaction networks: how could they help in searching for pro-longevity targets?

  Authors: Robi Tacutu, Arie Budovsky, Marina Wolfson, Vadim E Fraifeld

  Rejuvenation research. 04/2010; 13(2-3):373-7.

  In spite of enormous efforts and accumulated knowledge, our capabilities for tackling aging and age-related diseases (ARDs), and ultimately to promote longevity, are still very modest. What isIn spite of enormous efforts and accumulated knowledge, our capabilities for tackling aging and age-related diseases (ARDs), and ultimately to promote longevity, are still very modest. What is lacking--essential data on key players, efficient analytic tools, or both? Here we discuss how the existing data may be integrated and analyzed in the context of microRNA (miRNA)-regulated protein-protein interaction networks. The proposed model highlighted: (1) The strong molecular links between aging, longevity, and ARDs; (2) the possibility and even the preferability of initiating longevity-promoting interventions in adult life; (3) the potentially important role for miRNA- (or small interfering RNA [siRNA]) mediated targeting of certain genes with features of antagonistic pleiotropy; (4) the superiority of systemic interventions to the common single-target approach in curing ARDs and promoting longevity.

• Senescing cells share common features with dedifferentiating cells.

  Authors: Meytal Damri, Gila Granot, Hagit Ben-Meir, Yigal Avivi, Inbar Plaschkes, Vered Chalifa-Caspi, Marina Wolfson, Vadim Fraifeld, Gideon Grafi

  Rejuvenation research. 12/2009; 12(6):435-43.

  Dedifferentiation signifies the capacity of somatic cells to acquire stem cell-like properties. This process can be induced during normal development and as a response to various stimuli, such asDedifferentiation signifies the capacity of somatic cells to acquire stem cell-like properties. This process can be induced during normal development and as a response to various stimuli, such as pathogen infection and wounding. Dedifferentiation also characterizes the transition of differentiated leaf cells into protoplasts (plant cells devoid of cell walls), a transition accompanied by widespread chromatin decondensation. Transcriptome profiling of dedifferentiating protoplast cells revealed striking similarities with senescing cells; both display a large increase in the expression of genes of specific transcription factor (TF) families, including ANAC, WRKY, bZIP, and C2H2. Further analysis showed that leaves induced to senesce by exposure to dark display characteristic features of dedifferentiating cells, including chromatin decondensation, disruption of the nucleolus, and condensation of rRNA genes. Considering that premature senescence can be induced by various stress conditions both in plant and animal cells, our results suggest that the response of plant and also animal cells to certain stresses converges on cellular dedifferentiation whereby cells first acquire stem cell-like state prior to acquisition of a new cell fate (e.g., reentry into the cell cycle or death).

• NEDD9 Promotes Oncogenic Signaling in Mammary Tumor Development.

  Authors: Eugene Izumchenko, Mahendra K Singh, Olga V Plotnikova, Nadezhda Tikhmyanova, Joy L Little, Ilya G Serebriiskii, Sachiko Seo, Mineo Kurokawa, Brian L Egleston, Andres Klein-Szanto, Elena N Pugacheva, Richard R Hardy, Marina Wolfson, Denise C Connolly, Erica A Golemis

  Cancer research. 10/2009;

  In the past 3 years, altered expression of the HEF1/CAS-L/NEDD9 scaffolding protein has emerged as contributing to cancer metastasis in multiple cancer types. However, whereas some studies haveIn the past 3 years, altered expression of the HEF1/CAS-L/NEDD9 scaffolding protein has emerged as contributing to cancer metastasis in multiple cancer types. However, whereas some studies have identified elevated NEDD9 expression as prometastatic, other work has suggested a negative role in tumor progression. We here show that the Nedd9-null genetic background significantly limits mammary tumor initiation in the MMTV-polyoma virus middle T genetic model. Action of NEDD9 is tumor cell intrinsic, with immune cell infiltration, stroma, and angiogenesis unaffected. The majority of the late-appearing mammary tumors of MMTV-polyoma virus middle T;Nedd9(-/-) mice are characterized by depressed activation of proteins including AKT, Src, FAK, and extracellular signal-regulated kinase, emphasizing an important role of NEDD9 as a scaffolding protein for these prooncogenic proteins. Analysis of cells derived from primary Nedd9(+/+) and Nedd9(-/-) tumors showed persistently reduced FAK activation, attachment, and migration, consistent with a role for NEDD9 activation of FAK in promoting tumor aggressiveness. This study provides the first in vivo evidence of a role for NEDD9 in breast cancer progression and suggests that NEDD9 expression may provide a biomarker for tumor aggressiveness. [Cancer Res 2009;69(18):7198-206].

• The signaling hubs at the crossroad of longevity and age-related disease networks.

  Authors: Marina Wolfson, Arie Budovsky, Robi Tacutu, Vadim Fraifeld

  The international journal of biochemistry & cell biology. 09/2008;

  The established human age-related disease proteins (ARDPs) and longevity-associated proteins (LAPs) together with their first-order interacting partners form scale-free networks which significantlyThe established human age-related disease proteins (ARDPs) and longevity-associated proteins (LAPs) together with their first-order interacting partners form scale-free networks which significantly overlap. About half of the common proteins are involved in signal transduction. These proteins are strongly interconnected and in turn form a common signaling network which comprises over 40% of all hubs (proteins with multiple interactions) in the human interactome. Along with the insulin pathway, the common signaling network is remarkably enriched with the focal adhesion and adherens junction proteins whose relation to the control of lifespan is yet to be fully addressed. The examples of such candidate proteins include several hubs, focal adhesion kinase PTK2 and the extracellular proteins fibronectin FN1, paxillin PXN, and vinculin VCL. The results of the network-based analysis highlight the potential importance of these pathways, especially hubs, in linking the human longevity and age-related diseases.

• Modified pectin-based carrier for gene delivery: Cellular barriers in gene delivery course.

  Authors: Tali Katav, LinShu Liu, Tamar Traitel, Riki Goldbart, Marina Wolfson, Joseph Kost

  Journal of controlled release : official journal of the Controlled Release Society. 07/2008;

  The use of polysaccharides as DNA carriers has high potential for gene therapy applications. Pectin is a structural plant polysaccharide heterogeneous with respect to its chemical structure. ItThe use of polysaccharides as DNA carriers has high potential for gene therapy applications. Pectin is a structural plant polysaccharide heterogeneous with respect to its chemical structure. It contains branches rich in galactose residues which serve as potential ligands for membrane receptors interaction. In order to make the anionic pectin applicable for DNA complexation, it was modified with three different amine groups (cationic). Pectin-NH(2) was prepared by modifying the galacturonic acids carboxyl groups with primary amine groups and further modified to generate pectin-T (TN(+)H(CH(3))(2)) and pectin-NH(2)-Q (QN(+)(CH(3))(3)). All three modified pectins formed complexes with plasmid DNA as indicated by gel electrophoresis analysis. The size and morphology of pectin-NH(2)/DNA complexes were examined by transmission electron microscopy (TEM). Transfection experiments were carried out with human embryonic kidney cell lines (HEK293), using plasmid DNA encoding for green fluorescence protein (GFP). Transfection efficiency was analyzed by flow cytometry analysis, using FACS. Pectin-NH(2)-Q was the most efficient carrier. Addition of chloroquine ("lysosomotropic" agent) to transfection medium substantially enhanced the HEK293 transfection, indicating that endocytosis is the preferable internalization pathway and implies on the complex inability to escape the endosome. Pectin's galactose residues contribution to transfection was examined by inhibiting pectin binding to membrane receptors (galectins), using galactose and lactose as competitive inhibitors to this interaction. Resulting reduction of transfection efficiency demonstrated the importance of pectin's galactose residues to HEK293 transfection. Suggesting the modified pectin is a promising non-viral carrier for targeted gene delivery to cancer cells with galactose-binding lectins on their surface.

• Common gene signature of cancer and longevity.

  Authors: Arie Budovsky, Robi Tacutu, Hagai Yanai, Amir Abramovich, Marina Wolfson, Vadim Fraifeld

  Mechanisms of ageing and development. 05/2008;

  An association between aging/longevity and cancer has long been suggested, yet the evolutionary and molecular links between these complicated traits remain elusive. Here, we analyze the relationshipAn association between aging/longevity and cancer has long been suggested, yet the evolutionary and molecular links between these complicated traits remain elusive. Here, we analyze the relationship between longevity- and cancer-associated genes/proteins (LAGs/LAPs and CAGs/CAPs, respectively). Specifically, we address the following questions: (1) to what extent the CAGs and LAGs are evolutionary conserved and how they (or their orthologs) are related to each other in diverse species? (2) Could they act in cooperative manner at a protein level via protein-protein interactions (PPIs) and, if so, by forming a PPI network? We found that (i) the common genes (both LAGs and CAGs) show the same remarkable trend from yeast to humans: tumor suppressors are associated with lifespan extension, whereas the oncogenes are associated with reduced lifespan; (ii) LAPs and CAPs have a significantly higher average connectivity than other proteins in the human interactome; and (iii) LAPs and CAPs may act in cooperative manner via numerous direct and indirect PPIs between themselves and eventually by forming a PPI network. Altogether, the results of this study provide strong evidence for the existence of evolutionary and molecular links between longevity and cancer.

• [Cadherins in malignancies of the female genital tract]

  Authors: Benjamin Piura, Alex Rabinovich, Natalie Aizenberg, Marina Wolfson

  Harefuah. 05/2005; 144(4):261-5, 303, 302.

  Cadherins are a superfamily of adhesion molecules that mediate Ca++ -dependent cell-cell adhesion necessary for normal morphogenesis and maintenance of tissue integrity. A classical cadherinCadherins are a superfamily of adhesion molecules that mediate Ca++ -dependent cell-cell adhesion necessary for normal morphogenesis and maintenance of tissue integrity. A classical cadherin molecule, such as E-cadherin, is a glycoprotein made up of three parts: an extracellular portion composed of five identical domains, a transmembrane portion composed of a single domain and a cytoplasmic portion composed of two domains. The cytoplasmic portion is anchored by means of cytoplasmic catenins to the cytoskeleton. The three amino acids sequence, histidine, alanine and valine (HAV motif) located at the most external domain of the extracellular portion, plays a key role in homophilic recognition between two cadherin molecules and cell-cell adhesion. Loss of cell-cell adhesion may be a prerequisite for malignant transformation and the invasive behavior of malignant tumors. Research of cadherin in malignancies has attracted much attention since cadherins may be proven to be reliable markers of biological behavior and prognosis The studies on cadherin in malignancies of the female genital tract have shown the following results: 1) in malignant transformation of the ovarian surface epithelium (OSE) and in epithelial ovarian carcinoma confined to the ovary (Stage I) there is a switch from N-cadherin expression to E-cadherin expression; 2) In advanced-stage epithelial ovarian carcinoma (Stages II-IV) the results are at odds: some investigators have shown a loss of E-cadherin expression most often because of hypermethylation of the promoter region of the gene, while others have demonstrated an increase in E-cadherin expression; 3) In endometrial carcinoma, E-cadherin expression is decreasing and P-cadherin expression is increasing with worsening of histologic type and differentiation, increased penetration into the myometrium, spread beyond the uterus and involvement of pelvic lymph nodes; 4) In squamous cell carcinoma of the uterine cervix E-cadherin expression is decreasing with tumor progression and in adenocarcinoma of the uterine cervix P-cadherin expression is increasing with tumor progression. It is hoped that the development of drugs that amend cell-cell adhesion will improve the prognosis of patients in whom tumor progression is associated with decrease or loss of cadherin expression.

• p66ShcA and ageing: modulation by longevity-promoting agent aurintricarboxylic acid.

  Authors: Orli Sagi, Marina Wolfson, Natalie Utko, Khachik Muradian, Vadim Fraifeld

  Mechanisms of ageing and development. 03/2005; 126(2):249-54.

  Many mutations that extend the lifespan of the lower organisms such as C. elegans and Drosophila, are associated with signaling or apoptotic pathways. Recently, such a possibility was shown inMany mutations that extend the lifespan of the lower organisms such as C. elegans and Drosophila, are associated with signaling or apoptotic pathways. Recently, such a possibility was shown in mammals: p66ShcA-deficient mice were more resistant to oxidative stress and lived longer than the wild-type animals [Migliaccio, E., Giorgio, M., Mele, S., Pelicci, G., Reboldi, P., Randolfi, P.P., Lanfrancone, L., Pelicci, P.G., 1999. The p66Shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309-313]. There is evidence to implicate p66ShcA in age-related degenerative pathology, including atherosclerosis, sarcopenia, and Alzheimer's disease. We hypothesized that a low level expression of p66ShcA could be associated with longevity. Also, we suggested that the level of p66ShcA could be modulated by a putative longevity-promoting agent aurintricarboxylic acid [aurintricarboxylic acid (ATA); Fraifeld, V., Wolfson, M., Sagi, O., Seidman, R., Asraf, H., Utko, N., Muradian, K., 2002. Effects of anti-apoptotic agent aurintricarboxylic acid on longevity and longevity-associated processes. Biogerontology 3, 48]. We have found that: (i) the level of p66ShcA decreases with advanced age. Thirty-six-month-old mice have the lowest, whereas newborns have the highest p66ShcA levels; (ii) ATA significantly decreases the p66ShcA level in mouse lungs. In addition, the lifespan-prolongation effect of ATA in a Drosophila model was further validated. The results support the suggested role for the p66ShcA as one of the lifespan determinants in mammals; p66ShcA therefore represents a potential target for pharmacological longevity-promoting intervention.

• The Role of ERK 1/2 and p38 MAP-Kinase Pathways in Taxol-Induced Apoptosis in Human Ovarian Carcinoma Cells

  Authors: Rachel Seidman, Inna Gitelman, Orli Sagi, Susan Band Horwitz, Marina Wolfson

  Experimental Cell Research.

  Taxol is an anticancer agent of natural origin with significant activity against a number of human cancers including ovarian and breast carcinomas. Its cytotoxic activity has been attributed to itsTaxol is an anticancer agent of natural origin with significant activity against a number of human cancers including ovarian and breast carcinomas. Its cytotoxic activity has been attributed to its ability to stabilize microtubules and to promote microtubule assembly. Recently it has become clearer that Taxol has additional activities including effects in cell signalingand gene expression. We have shown previouslythat Taxol activates ERK 1/2 MAP-kinases and results in the formation of GRB2/SHC complexes in murine macrophage-like RAW 267.4 cells. Here we demonstrate that Taxol activates ERK 1/2 and p38 MAP-kinases in human ovarian carcinoma cells with distinct kinetics. Activation of ERK1/2 has been observed at low concentrations of Taxol (1–100 nM) within 0.5–6 h, whereas longer exposure(24 h) to nanomolar concentrations of Taxol resulted in an abrogation of the ERK1/2 phosphorylation/activation. Higher concentrations (1–10 μM) resulted in a sharp inhibition of ERK1/2 activity. p38 kinase was activated by high concentrations (1–10 μM) of Taxol within 2 h and remained active for more than 24 h. The kinetic studies showed that these effects of Taxol coincided with an inhibition of proliferation, and the onset of apoptosis. The appearance of the fragmented chromatin visualized by DAPIstaining, and DNA fragments seen on an agarose gel, coincided with the decrease in ERK1/2 activation and concomitant increase of the level of activep38 MAPK. The inhibitor PD98059 abrogated ERK 1/2 activation and increased the cytotoxic effect of Taxol. An inhibitor of p38 kinase, SB203580, protected the cells partially from Taxol and, unexpectedly, activated ERK 1/2 kinases. We conclude that the alternative use of ERK1/2 and p38 MAP-kinase pathways may be necessary for the transition from proliferation state to Taxol-induced apoptosisin human ovarian carcinoma cells.

• Common gene signature of cancer and longevity

  Authors: Arie Budovsky, Robi Tacutu, Hagai Yanai, Amir Abramovich, Marina Wolfson, Vadim Fraifeld

  Mechanisms of Ageing and Development.

  An association between aging/longevity and cancer has long been suggested, yet the evolutionary and molecular links between these complicated traits remain elusive. Here, we analyze the relationshipAn association between aging/longevity and cancer has long been suggested, yet the evolutionary and molecular links between these complicated traits remain elusive. Here, we analyze the relationship between longevity- and cancer-associated genes/proteins (LAGs/LAPs and CAGs/CAPs, respectively). Specifically, we address the following questions: (1) to what extent the CAGs and LAGs are evolutionary conserved and how they (or their orthologs) are related to each other in diverse species? (2) Could they act in cooperative manner at a protein level via protein–protein interactions (PPIs) and, if so, by forming a PPI network? We found that (i) the common genes (both LAGs and CAGs) show the same remarkable trend from yeast to humans: tumor suppressors are associated with lifespan extension, whereas the oncogenes are associated with reduced lifespan; (ii) LAPs and CAPs have a significantly higher average connectivity than other proteins in the human interactome; and (iii) LAPs and CAPs may act in cooperative manner via numerous direct and indirect PPIs between themselves and eventually by forming a PPI network. Altogether, the results of this study provide strong evidence for the existence of evolutionary and molecular links between longevity and cancer.