Abstract |
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, PKCzeta down-regulation is shown to be a critical determinant of cell migration. Transfection of high-motility cells with either wild-type PKCzeta or its regulatory domain suppresses migration. Known to bind to the regulatory domain of PKCzeta, the proapoptotic protein prostate apoptosis response-4 (Par-4) coimmunoprecipitates with PKCzeta 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 PKCzeta), whereas high-motility cells (which express low levels of PKCzeta) are unaffected by Par-4 overexpression. It is proposed that in nonmetastatic cells, the PKCzeta Par-4 complex provides a brake on migration that is released by melanin precursors that initiate PKCzeta down-regulation. Elevation of PKCzeta 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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Authors | E Sanz-Navares, N Fernandez, M G Kazanietz, S A Rotenberg |
Journal | Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research
(Cell Growth Differ)
Vol. 12
Issue 10
Pg. 517-24
(Oct 2001)
ISSN: 1044-9523 [Print] United States |
PMID | 11682463
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Apoptosis Regulatory Proteins
- Carrier Proteins
- DNA, Complementary
- Intracellular Signaling Peptides and Proteins
- Melanins
- prostate apoptosis response-4 protein
- Tyrosine
- Phenylalanine
- protein kinase C zeta
- Protein Kinase C
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Topics |
- Animals
- Apoptosis Regulatory Proteins
- Blotting, Western
- Carrier Proteins
(metabolism)
- Cell Adhesion
- Cell Line
- Cell Movement
- Cell Separation
- Cells, Cultured
- DNA, Complementary
(metabolism)
- Down-Regulation
- Intracellular Signaling Peptides and Proteins
- Melanins
(biosynthesis)
- Melanoma, Experimental
- Mice
- Mutagenesis, Site-Directed
- Neoplasm Metastasis
- Phenylalanine
(metabolism)
- Precipitin Tests
- Protein Kinase C
(metabolism)
- Structure-Activity Relationship
- Transfection
- Tumor Cells, Cultured
- Tyrosine
(metabolism)
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