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Biomedical subjects

S M Frisch

Publications and source records attributed to S M Frisch.

At least 19 recordsLinked to original sources
PubMed2001

Tumor suppression activity of adenovirus E1a protein: anoikis and the epithelial phenotype.

Adenovirus E1a proteins reverse-transform diverse human tumor cells in culture. This has stimulated interest in the arenas of clinical and basic cancer research. Clinically, cancer gene therapy trials on E1a are in progress, and drug discovery strategies based on E1a are being considered. Biologically, the effect of E1a is unique in that it overrides most or all oncogenic signaling pathways to yield nontumorigenic cells. Apparently, this is a consequence of the ability of E1a to reprogram transcription in tumor cells so as to produce an epithelial phenotype that is refractory to oncogenic growth stimulation. The molecular basis for this effect is emerging.

Adenovirus E1A Proteins↗
PubMed2001

Anoikis mechanisms.

Anoikis is defined as apoptosis that is induced by inadequate or inappropriate cell-matrix interactions. It is involved in a wide diversity of tissue-homeostatic, developmental and oncogenic processes. The central problem of anoikis is to understand how integrin-mediated cell adhesion signals control the apoptotic machinery. In particular, the initiation of the caspase cascade in anoikis remains to be explained.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Evidence for a function of CtBP in epithelial gene regulation and anoikis.

Previously, we reported that adenovirus E1a protein behaves as a tumor suppressor in human cells. It apparently functions by transcriptionally inducing an array of epithelial cell adhesion genes, while repressing other cell-type specific genes, thus producing an epithelial phenotype. Concomitantly, the cells become sensitive to anoikis (apoptosis of epithelial cells detached from extracellular matrix), potentially causing tumor suppression. E1a protein interacts with the nuclear acetylases p300, CBP and P/CAF, and also with the co-repressor protein CtBP. In this study, we have determined the role of these interactions in E1a's phenotypic effects on human tumor cells. The results indicate that E1a's interaction with CtBP activates at least three epithelial cell adhesion gene promoters. The E-cadherin repressor appeared to be the CtBP-interacting protein delta EF1/ZEB, which bound the ras-repressible E-boxes of the E-cadherin promoter. The E1a-CtBP interaction also contributed to anoikis-sensitization. E1a's interactions with the nuclear acetylases conferred epithelial morphologies but did not activate epithelial genes. These latter interactions did not sensitize tumor cells to anoikis but nevertheless conferred tumor suppression. These results implicate CtBP as an antagonist of the epithelial phenotype and anoikis. They also indicate a new but undefined role for nuclear acetylases in maintaining the transformed phenotype.

Adenovirus E1A Proteins↗
PubMed2000

Anoikis.

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Animals↗
PubMed1999

Evidence for a function of death-receptor-related, death-domain-containing proteins in anoikis.

Normal epithelial cells undergo apoptosis if integrinmediated matrix contacts are lost, in a process termed 'anoikis'. Anoikis prevents shed epithelial cells from colonizing elsewhere, and is thus essential for maintaining appropriate tissue organisation. Aberrant oncogenes or tumor suppressor genes can cause resistance to anoikis, thereby contributing substantially to malignancy. Apoptosis is mediated by a well-ordered signaling cascade, which involves activation of intracellular proteases known as caspases. However, the mechanism by which the caspase cascade is initiated following cell-matrix detachment is unknown. We have hypothesized that death receptor activation might be involved in anoikis. To test this hypothesis, we developed a transient assay for anoikis and used it to assay the effects of proteins that block the function of domains found within death receptors known as death domains. In this assay, silencer of death domains (SODD) and dominant-negative FAS-associated death domain protein (FADD) efficiently inhibited anoikis in Madin-Darby canine kidney (MDCK) cells. The protective activity of SODD required its BAG domain, which interacts with the heat shock proteins hsp70 and hsc70, and inhibits the chaperone activity of the latter. Both caspase 8, which physically associates with death receptors, and cleavage of the caspase-8 substrate BID, were activated by cell-matrix detachment. These findings indicate a role for death receptors or proteins with related death domains in triggering anoikis.

Animals↗
PubMed1997

The regulation of anoikis: MEKK-1 activation requires cleavage by caspases.

Certain cell types undergo apoptosis when they lose integrin-mediated contacts with the extracellular matrix ("anoikis"). The Jun N-terminal kinase (JNK) pathway is activated in and promotes anoikis. This activation requires caspase activity. We presently report that a DEVD motif-specific caspase that cleaves MEKK-1 specifically is activated when cells lose matrix contact. This cleavage is required for the activation of the kinase activity. When overexpressed, the MEKK-1 cleavage product stimulates apoptosis; the wild-type, full-length MEKK-1 sensitizes cells to anoikis; and a cleavage-resistant mutant of MEKK-1 partially protects cells against anoikis. The cleavage-resistant or kinase-inactive mutants also prevent caspase-7 from being activated completely. Thus, caspases can induce apoptosis by activating MEKK-1, which in turn activates more caspase activity, comprising a positive feedback loop.

Amino Acid Sequence↗
PubMed1997

The epithelial cell default-phenotype hypothesis and its implications for cancer.

The expression of epithelial cell adhesion and cytoskeletal genes is orchestrated by an apparently unique set of rules. No tissue-specific transactivator proteins have been found to drive them; only ubiquitous factors are utilized. In non-epithelial cells, they are actively repressed. Moreover, it was recently found that a single protein (adenovirus E1a) coordinately represses non-epithelial genes while inducing epithelial genes. A simple model is offered to explain how epithelial gene expression is coordinated. Under this model, the epithelial cell gene expression program is a transcriptional 'default'; that is, it occurs in the absence of tissue-specific transactivation. Conversion to this default requires only that mesenchymal transactivators are not expressed, or that central 'integrator' proteins are inactive. In their absence, mesenchymal gene expression cannot occur. Moreover, because the repressors cease to be expressed, the epithelial genes are induced. Oncogenes generally cause the breakdown of the epithelial phenotype--generating carcinomas--so genes such as E1a that cause epithelial conversion may prove useful for both understanding and controlling cancer.

Animals↗
PubMed1997

Integrins and anoikis.

The loss of integrin-mediated cell-matrix contact induces apoptosis ('anoikis') in certain cell types. Recently it has been shown that protein kinase signaling pathways control anoikis both positively and negatively. Focal adhesion kinase, when activated by integrins, can suppress anoikis. Phosphatidylinositol 3-kinase and the AKT oncoprotein may mediate the anoikis-suppressing effects of focal adhesion kinase. Conversely, the stress-activated protein kinase/Jun amino-terminal kinase pathway promotes anoikis. Latest results indicate that caspase-mediated cleavage of the first component of this latter pathway, MEKK-1, may trigger activation of this pathway in anoikis. In addition, certain integrins may regulate bcl-2 expression levels, possibly adjusting the threshold for anoikis.

Animals↗
PubMed1996

Expression of the integrin alpha 5 subunit in HT29 colon carcinoma cells suppresses apoptosis triggered by serum deprivation.

It is clear that certain integrins can regulate the growth of tumors, probably by contributing to signal transduction processes. In the present study we have used HT29 human colon carcinoma cells stably transfected with human cDNA for the integrin alpha 5 subunit and studied the effects of alpha 5 expression on the induction of apoptosis. We observe that apoptosis can be triggered in HT29 cells by removal of serum and that this process can be suppressed by the stable expression of full-length integrin alpha 5 subunits. While the mechanism underlying this effect is still unclear, these observations suggest that the alpha 5 beta 1 integrin plays an important role in modulating tumor cell responses to growth factors and nutrients.

Antigens, CD↗
PubMed1996

Reversal of malignancy by the adenovirus E1a gene.

Tumor suppressor genes such as Rb and p53 usually kill tumor cells when overexpressed ectopically. This is a consequence of their normal cell cycle regulatory functions. By contrast, the E1a gene of adenovirus, a common cold virus, converts tumor cells into viable normal cells. This has advantages for investigation and control of cancer. In particular, E1a is a master programmer of the epithelial phenotype. This provides a new tool for understanding the molecular basis of the epithelial-mesenchymal transition, and how it goes awry in cancer cells. Furthermore, epithelial cells are sensitive to a form of apoptosis - 'anoikis' - that is induced by detachment from extracellular matrix. This property confers strict anchorage-dependence. Transcriptional programming, by E1a or the formation of cell-cell junctional complexes, programs epithelial cells to be sensitive to anoikis.

Adenovirus E1A Proteins↗
PubMed1996

Control of adhesion-dependent cell survival by focal adhesion kinase.

The interactions of integrins with extracellular matrix proteins can activate focal adhesion kinase (FAK) and suppress apoptosis in normal epithelial and endothelial cells; this subset of apoptosis has been termed "anoikis." Here, we demonstrate that FAK plays a role in the suppression of anoikis. Constitutively activated forms of FAK rescued two established epithelial cell lines from anoikis. Both the major autophosphorylation site (Y397) and a site critical to the kinase activity (K454) of FAK were required for this effect. Activated FAK also transformed MDCK cells, by the criteria of anchorage-independent growth and tumor formation in nude mice. We provide evidence that this transformation resulted primarily from the cells' resistance to anoikis rather than from the activation of growth factor response pathways. These results indicate that FAK can regulate anoikis and that the conferral of anoikis resistance may suffice to transform certain epithelial cells.

Animals↗
PubMed1996

A role for Jun-N-terminal kinase in anoikis; suppression by bcl-2 and crmA.

The disruption of interactions between extracellular matrix and specific cognate integrins triggers apoptosis in epithelial cells, in a process termed "anoikis." To understand anoikis, the connections between epithelial cell integrin signaling and the apoptosis-regulatory proteins are being explored. We report herein that early after detachment from matrix, epithelial cells activate Jun-N-Terminal Kinases (JNKs; alternatively known as Stress-activated Protein Kinases), which are also activated by other apoptotic stimuli. The activity of this pathway was required for anoikis. Another early response to cell suspension was the activation of the ICE-related cysteine protease, ICE/LAP3; this activation and anoikis were suppressed by the ICE-protease inhibitor, crmA. The overexpression of bcl-2 suppressed ICE/LAP3 activation as well. Surprisingly, bcl-2 and crmA attenuated the activation of JNKs following cell suspension, suggesting that the JNK pathway is regulated directly or indirectly by proteolysis. In addition, the blockage of the JNK pathway attenuated the activation of ICE/LAP3, suggesting a positive feedback loop between the ICE and JNK systems. These results indicate the following sequence of information flow in anoikis: integrins-->bcl-2/bax-->(ICE-proteases<-->JNK)-->apopt osis. Cell-cell interactions, which were previously shown to sensitize cells to anoikis, caused bcl-2 mRNA to be downregulated, a permissive event for downstream apoptotic signaling.

Animals↗
PubMed1995

Adenovirus E1a-mediated tumor suppression by a c-erbB-2/neu-independent mechanism.

We reported previously that the adenovirus E1a gene reversed the transformed phenotype of one human melanoma and one fibrosarcoma cell line (S. Frisch, Proc. Natl. Acad. Sci. USA, 88: 9077-9081, 1991). To determine the generality of the tumor suppression effects of E1a, a diversity of tumor cell lines, including A204 rhabdomyosarcoma, RD rhabdomyosarcoma, Saos-2 osteosarcoma, NCI-H23 non-small cell lung carcinoma, MDA-MB435S breast carcinoma, and ras-transformed MDCK kidney epithelial cells, were infected with a retrovirus bearing the 12S E1a coding sequence. We demonstrate here that the expression of E1a severely reduced the anchorage-independent and tumorigenic growth of these cell lines without affecting their growth under normal culture conditions. The parental tumor cells used in this study did not overexpress c-erbB-2/neu, and E1a did not affect its expression in these cells. Thus, tumor suppression by E1a can operate in a wide variety of human tumor cells by c-erbB-2/neu-independent mechanisms. E1a also sensitized these cell lines to the cytotoxic effects of the anticancer drugs etoposide and cisplatin. The results suggest that E1a could prove useful for the gene therapy of a wide variety of human cancers.

Adenovirus E1A Proteins↗
PubMed1994

Disruption of epithelial cell-matrix interactions induces apoptosis.

Cell-matrix interactions have major effects upon phenotypic features such as gene regulation, cytoskeletal structure, differentiation, and aspects of cell growth control. Programmed cell death (apoptosis) is crucial for maintaining appropriate cell number and tissue organization. It was therefore of interest to determine whether cell-matrix interactions affect apoptosis. The present report demonstrates that apoptosis was induced by disruption of the interactions between normal epithelial cells and extracellular matrix. We have termed this phenomenon "anoikis." Overexpression of bcl-2 protected cells against anoikis. Cellular sensitivity to anoikis was apparently regulated: (a) anoikis did not occur in normal fibroblasts; (b) it was abrogated in epithelial cells by transformation with v-Ha-ras, v-src, or treatment with phorbol ester; (c) sensitivity to anoikis was conferred upon HT1080 cells or v-Ha-ras-transformed MDCK cells by reverse-transformation with adenovirus E1a; (d) anoikis in MDCK cells was alleviated by the motility factor, scatter factor. The results suggest that the circumvention of anoikis accompanies the acquisition of anchorage independence or cell motility.

Animals↗
PubMed1994

E1a induces the expression of epithelial characteristics.

Cells closely resembling epithelia constitute the first specific cell type in a mammalian embryo. Many other cell types emerge via epithelial-mesenchymal differentiation. The transcription factors and signal transduction pathways involved in this differentiation are being elucidated. I have previously reported (Frisch, 1991) that adenovirus E1a is a tumor suppressor gene in certain human cell lines. In the present report, I demonstrate that E1a expression caused diverse human tumor cells (rhabdomyosarcoma, fibrosarcoma, melanoma, osteosarcoma) and fibroblasts to assume at least two of the following epithelial characteristics: (a) epithelioid morphology; (b) epithelial-type intercellular adhesion proteins localized to newly formed junctional complexes; (c) keratin-containing intermediate filaments; and (d) down-regulation of non-epithelial genes. E1a thus appeared to partially convert diverse human tumor cells into an epithelial phenotype. This provides a new system for molecular analysis of epithelial-mesenchymal interconversions. This effect may also contribute to E1a's tumor suppression activity, possibly through sensitization to anoikis (Frisch, S.M., and H. Francis, 1994. J. Cell Biol. 124:619-626).

Adenovirus E1A Proteins↗