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Reexpression of the Major Protein Kinase C Substrate, SSeCKS, Suppresses v-src-induced Morphological Transformation and Tumorigenesis¹

Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029-6574

SSeCKS (pronounced essex) encodes a major protein kinase C substrate, the expression of which is down-regulated in src- and ras-trans-formed rodent fibroblasts but not in raf-transformed rodent fibroblasts (X. Lin et al., Mol. Cell. Biol., 15: 2754–2762, 1995). Using a panel of ras-transformed or revertant Rat-6 cells that exhibit selective parameters of transformation, we show that down-regulation of SSeCKS correlates with anchorage-independent growth. Cotransfection of NIH3T3 fibro-blasts with an SSeCKS expression plasmid decreased 6–30-fold the ability of a v-src expressor plasmid to induce colonies in soft agar. To differentiate between possible tumor suppressive or growth-inhibitory effects of SSeCKS, we developed conditionally transformed cell lines (expressing ts72v-src) with tetracycline-regulated SSeCKS expression. SSeCKS suppressed the ability of v-src to induce increased cellular refractility, focus formation, soft agar colony formation, in vitro invasiveness in Matrigel, and growth in low serum (0.5%) but did not inhibit cell proliferation in high serum (10%) at the permissive (35°C) temperature for src kinase activity. However, at the nonpermissive (39.5°C) temperature, SSeCKS induced growth arrest. SSeCKS expression did not affect: (a) the protein level, in vivo or in vitro kinase activity of ts72src; (b) the activity of jun NH₂-terminal kinase; and (c) the level of mitogen-activated protein kinase (extracellular signal-regulated kinase 2) protein. However, extracellular signal-regulated kinase 2 activity was induced 5–10-fold by SSeCKS in the presence of active src. SSeCKS reversed the ability of v-src to decrease the formation of vinculin-associated adhesion plaques, actin-based stress fibers, and filopodia structures. These data suggest a tumor suppressive role for SSeCKS via the control of cytoskeletal architecture and cell signaling.

¹ This work was supported by NIH Grant CA65787 (to I. H. G.).

² To whom requests for reprints should be addressed, at Department of Microbiology, Box 1124, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574. Phone: (212) 241-3749; Fax: (212) 534-1684; E-mail: igelman@smtplink.mssm.edu.

Received 11/26/96. Accepted 4/ 3/97.

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