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Am J Physiol Cell Physiol 285: C1386-C1396, 2003. First published August 13, 2003; doi:10.1152/ajpcell.00338.2002
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GROWTH, DIFFERENTIATION, AND APOPTOSIS

VACM-1, a cul-5 gene, inhibits cellular growth by a mechanism that involves MAPK and p53 signaling pathways

C. Van Dort,1 P. Zhao,2 K. Parmelee,1 B. Capps,1 A. Poel,1 L. Listenberger,1 J. Kossoris,1 B. Wasilevich,1 D. Murrey,1 P. Clare,3 and M. Burnatowska-Hledin1

1Departments of Biology and Chemistry, Peale Science Center, Hope College, Holland, 49422-9000; 2Van Andel Research Institute, Grand Rapids 49503; and 3Pfizer Co., Kalamazoo, Michigan 49007

Submitted 22 July 2002 ; accepted in final form 25 July 2003

Vasopressin-activated Ca2+-mobilizing (VACM)-1 gene product is a 780-amino acid membrane protein that shares sequence homology with cullins, a family of genes involved in the regulation of cell cycle. However, when expressed in vitro, VACM-1 attenuates basal and vasopressin- and forskolin-induced cAMP production. Mutating the PKA-dependent phosphorylation site in the VACM-1 sequence (S730AVACM-1) prevents this inhibitory effect. To further examine the biological role of VACM-1, we studied the effect of VACM-1 and S730AVACM-1 proteins on cellular proliferation and gene expression in Chinese hamster ovary and COS-1 cells. Cellular proliferation of VACM-1-expressing cell lines was significantly lower compared with that of the vector-transfected cells, whereas it was significantly increased in S730AVACM-1-derived cell lines. Furthermore, expression of VACM-1 but not S730AVACM-1 protein retarded cytokinesis and prevented MAPK phosphorylation. Screening with the Human PathwayFinder-1 GEArray system and subsequent Western blot analysis demonstrated that VACM-1 induces p53 mRNA and protein expression. In summary, VACM-1 inhibits cellular growth by a mechanism that involves cAMP, MAPK phosphorylation, and p53 expression.

mitogen-activated protein kinase; cytokinesis; vasopressin-activated calcium-mobilizing receptor


Address for reprint requests and other correspondence: M. Burnatowska-Hledin, Dept. of Biology, Peale Science Center, Hope College, Holland, MI 49422-9000 (E-mail: Hledin{at}hope.edu).






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