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Cell Growth & Differentiation Vol. 12, 517-524, October 2001
© 2001 American Association for Cancer Research

Atypical Protein Kinase C{zeta} Suppresses Migration of Mouse Melanoma Cells1

Eduardo Sanz-Navares, Nieves Fernandez, Marcelo G. Kazanietz and Susan A. Rotenberg2

Department of Chemistry and Biochemistry [E. S-N., S. A. R.] and Graduate Center [E. S-N.], Queens College of the City University of New York, Flushing, New York 11367, and Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania [N. F., M. G. K.]

Mouse melanoma B16 F1 cells cultured in RPMI 1640 supplemented with the melanin precursors tyrosine and phenylalanine display increased melanin levels and elevated migration while down-regulating protein kinase C (PKC){zeta} to low levels. Although control experiments rule out a direct role by melanin, PKC{zeta} down-regulation is shown to be a critical determinant of cell migration. Transfection of high-motility cells with either wild-type PKC{zeta} or its regulatory domain suppresses migration. Known to bind to the regulatory domain of PKC{zeta}, the proapoptotic protein prostate apoptosis response-4 (Par-4) coimmunoprecipitates with PKC{zeta} as a 47-kDa protein. Transfection of Par-4 (or its leucine zipper element) further suppresses migration of low-motility cells (which express high levels of PKC{zeta}), whereas high-motility cells (which express low levels of PKC{zeta}) are unaffected by Par-4 overexpression. It is proposed that in nonmetastatic cells, the PKC{zeta} Par-4 complex provides a brake on migration that is released by melanin precursors that initiate PKC{zeta} down-regulation. Elevation of PKC{zeta} in melanoma cells, or preventing its down-regulation through the dietary restriction of tyrosine and phenylalanine, may therefore control metastatic behavior.







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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 2001 by the American Association of Cancer Research.