The gep proto-oncogene Gα12 mediates LPA-stimulated activation of CREB in ovarian cancer cells.
Lysophosphatidic acid (LPA) plays a critical role in the pathophysiology of ovarian cancers. Previous studies have shown that LPA stimulates the proliferation of ovarian cancer cells via Gα12. The present study utilizing Protein/DNA array analyses of LPA-stimulated HeyA8 cells in which the expression of Gα12 was silenced, demonstrates for the first time that Gα12-dependent mitogenic signaling by LPA involves the atypical activation cAMP-response element binding protein (CREB). Results indicate that the robust activation of CREB by LPA is an early event that can be monitored by the phosphorylation of SER133 of CREB as early as 3min. The findings that the expression of the constitutively activated mutant of Gα12 stimulates CREB even in the absence of LPA in multiple ovarian cancer cell lines confirm the direct role of Gα12 in the activation of CREB. This is further substantiated by the observation that the silencing of Gα12 drastically attenuates LPA-stimulated phosphorylation of CREB. Our results also establish that LPA-Gα12-dependent activation of CREB is through a cAMP-independent, but Ras-ERK-dependent mechanism. More significantly, our findings indicate that the expression of the dominant negative S133A mutant of CREB leads to a reduction in LPA-stimulated proliferation of HeyA8 ovarian cancer cells. Thus, results presented here demonstrate for the first time that CREB is a critical signaling node in LPA-LPAR and Gα12/gep proto-oncogene stimulated oncogenic signaling in ovarian cancer cells.
Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC West 1468, Oklahoma City, OK 73104, United States; College of Pharmacy, Seoul National University, Seoul, South Korea; Department of Cell Biology, The University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC West 1468, Oklahoma City, OK 73104, United States.
Ji Hee
JH
Ha
Jeremy D
JD
Ward
Lakshmi
L
Varadarajalu
Sang Geon
SG
Kim
Danny N
DN
Dhanasekaran
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism*; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D008246:Lysophospholipids; C000715470:MAS1 protein, human; D050505:Mutant Proteins; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors; D010768:Phosphoserine; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D018631:ras Proteins; C032881:lysophosphatidic acid
CREB; Cyclic-AMP Response Element Binding Protein; ERK; Extracellular-signal Regulated Kinase; Gα(12); LPA; LPA-receptor; LPAR; Lysophosphatidic Acid; MSK1; Mitogen and Stress-activated protein Kinase-1; Oncogene; Ovarian cancer; p38-Mitogen-activated Protein Kinase; p38MAPK