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J. Biol. Chem., Vol. 281, Issue 3, 1840-1852, January 20, 2006

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Opposite Roles of FAP-1 and Dynamin in the Regulation of Fas (CD95) Translocation to the Cell Surface and Susceptibility to Fas Ligand-mediated Apoptosis^*

Vladimir N. Ivanov1, Ze'ev Ronai, and Tom K. Hei¶

From the Center for Radiological Research, College of Physicians and Surgeons and the ^¶Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032 and the Signal Transduction Program, The Burnham Institute, La Jolla, California 92037

Human melanoma is the most aggressive form of skin cancer and is extremely resistant to radiation and chemotherapy. One of the critical parameters of this resistance is down-regulation of Fas (CD95) cell-surface expression. Using TIG3 normal human fibroblasts and human melanoma cell lines, we investigated transcriptional regulation of FAP-1, a regulator of Fas translocation in the cell. Protein-tyrosine phosphatase FAP-1 (PTPN13, PTP-BAS) interacts with human Fas protein and prevents its export from the cytoplasm to the cell surface. In contrast, dynamin-2 facilitates Fas protein translocation from the Golgi apparatus via the trans-Golgi network to the cell surface. Suppression of dynamin functions by dominant negative dynamin K44A blocks Fas export, whereas the down-regulation of FAP-1 expression by specific RNA interference restores Fas export (a phenomenon that could still be down-regulated in the presence of dominant-negative dynamin). Based on the FAP-1- and dynamin-dependent regulation of Fas translocation, we have created human melanoma lines with different levels of surface expression of Fas. Treatment of these melanoma lines with soluble Fas ligand resulted in programmed cell death that was proportional to the pre-existing levels of surface Fas. Taking into consideration the well known observations that FAP-1 expression is often up-regulated in metastatic tumors, we have established a causal connection between high basal NF-B transcription factor activity (which is a hallmark of many types of metastatic tumors) and NF-B-dependent transcriptional regulation of FAP-1 gene expression that finally restricts Fas protein trafficking, thereby, facilitating the survival of cancer cells.

Received for publication, September 7, 2005 , and in revised form, October 24, 2005.

^* This work was supported by National Institutes of Health Grant ES 11804, Superfund Grant P42 ES 10349, and Environmental Center Grant P30 ES 09089. We have no financial conflicts of interest. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Center for Radiological Research, Columbia University, VC11–204, 630 West 168th St., New York, NY 10032. Tel.: 212-305-0846; Fax: 212-305-3229; E-mail: vni3{at}columbia.edu.

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