Suppression of the p53-dependent replicative senescence response by lysophosphatidic acid signaling.
Lysophosphatidic acid (LPA) is a lipid mediator of a large number of biological processes, including wound healing, brain development, vascular remodeling, and tumor progression. Its role in tumor progression is probably linked to its ability to induce cell proliferation, migration, and survival. In particular, the ascites of ovarian cancers is rich in LPA and has been implicated in growth and invasion of ovarian tumor cells. LPA binds to specific G protein-coupled receptors and thereby activates multiple signal transduction pathways, including those initiated by the small GTPases Ras, Rho, and Rac. We report here a genetic screen with retroviral cDNA expression libraries to identify genes that allow bypass of the p53-dependent replicative senescence response in mouse neuronal cells, conditionally immortalized by a temperature-sensitive mutant of SV40 large T antigen. Using this approach, we identified the LPA receptor type 2 (LPA(2)) and the Rho-specific guanine nucleotide exchange factor Dbs as potent inducers of senescence bypass. Enhanced expression of LPA(2) or Dbs also results in senescence bypass in primary mouse embryo fibroblasts in the presence of wild-type p53, in a Rho GTPase-dependent manner. Our results reveal a novel and unexpected link between LPA signaling and the p53 tumor-suppressive pathway.
Kortlever
Roderik M
RM
Division of Molecular Carcinogenesis, Center for Cancer Genomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Brummelkamp
Thijn R
TR
van Meeteren
Laurens A
LA
Moolenaar
Wouter H
WH
Bernards
René
R
D000818:Animals; D000952:Antigens, Polyomavirus Transforming; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015723:Gene Library; D049452:Green Fluorescent Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D054792:Muscle, Striated / Q000166:cytology / Q000378:metabolism; D011087:Polycythemia Vera / Q000378:metabolism / Q000473:pathology; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; D020662:Guanine Nucleotide Exchange Factors; D008246:Lysophospholipids; C092132:Mcf2l protein, mouse; D049368:Receptors, Lysophosphatidic Acid; D064067:Rho Guanine Nucleotide Exchange Factors; D016159:Tumor Suppressor Protein p53; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D020741:rho GTP-Binding Proteins; C032881:lysophosphatidic acid