|
General Comment |
The lysolipid mediator lysophosphatidic acid (LPA) is generated by phospholipase cleavage of membrane
phospholipids from stimulated cells and platelets. LPA is present at micromolar concentrations in serum, and it elicits
diverse biologic functions, including proliferation, platelet aggregation, smooth muscle contraction, inhibition of
neuroblastoma cell differentiation, chemotaxis, and tumor cell invasion. LPA and the structurally related lysolipid
mediator sphingosine 1-phosphate (S1P) signal cells through a set of G protein-coupled receptors known as EDG
receptors.
NCBI Summary:
This gene encodes a member of family I of the G protein-coupled receptors, as well as the EDG family of proteins. This protein functions as a lysophosphatidic acid (LPA) receptor and contributes to Ca2+ mobilization, a critical cellular response to LPA in cells, through association with Gi and Gq proteins. An alternative splice variant has been described but its full length sequence has not been determined. [provided by RefSeq, Jul 2008]
|
|
Comment |
Expression of factors involved in apoptosis and cell survival is correlated with enzymes synthesizing lysophosphatidic acid and its receptors in granulosa cells originating from different types of bovine ovarian follicles. Sinderewicz E et al. (2017) Lysophosphatidic acid (LPA) regulates reproductive processes in the cow. Ovarian granulosa cells play a pivotal role in follicle growth and development. Nevertheless, the role of LPA in the local regulation of granulosa cell function in different follicle categories in the bovine ovary has not been investigated. Ovarian follicles were divided into healthy, transitional and atretic categories. The expression levels of AX, PLA2, LPARs and factors involved in apoptosis and cell survival processes in granulosa cells in different types of follicles were measured by real-time PCR. The correlations between the expression levels of AX, PLA2, LPARs and the examined factors were measured. The immunolocalization of AX, PLA2 and LPARs in different ovarian follicles was examined by immunohistochemistry. Statistical analyses were conducted in GraphPad using a one-way ANOVA followed by the Kruskal-Wallis multiple comparison test or a correlation analysis followed by Pearson's test. The expression levels of AX, PLA2 and LPARs, with the major role of LPAR2 and PLA2, were found in the granulosa cells originating from different follicle types. The expression levels of the factors involved in cell apoptosis (TNFα and its receptors, FAS, FASL, CASP3, CASP8, β-glycan, and DRAK2) were significantly higher in the granulosa cells of the atretic follicles compared to the healthy follicles. A number of correlations between LPARs, AX, PLA2 and factors associated with apoptosis were observed in the atretic but not in the healthy follicles. A greater expression of the factors involved in differentiation and proliferation in the granulosa cells (DICE1 and SOX2) was found in the healthy follicles in comparison with the atretic. A number of correlations between LPARs, AX, PLA2 and the factors associated with cell survival were observed in the healthy but not in the atretic follicles. Granulosa cells are the target of LPA action and the source of LPA synthesis in the bovine ovarian follicle. We suggest that the participation of LPA in apoptosis in the atretic follicles mainly occurs through the regulation of TNF-α-dependent and caspase-induced pathways. In the transitional follicles, LPA might influence the inhibins to shift the balance between the number of healthy and atretic follicles. In the healthy follicle type, LPA, acting via LPAR1, might regulate MCL1 and estradiol-stimulating ERβ mRNA expression, leading to the stimulation of anti-apoptotic processes in the granulosa cells and their differentiation and proliferation.//////////////////
Fang X, et al 2000 reported the role of lysophospholipid growth factors in the initiation, progression,
metastases, and management of ovarian cancer.
Levels of lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC) are
elevated in the plasma and ascites of ovarian cancer patients, but not in most other
tumor types. LPA increases cell proliferation, cell survival, resistance to
cisplatin, cell shrinkage, and production of vascular endothelial growth factor,
urokinase plasminogen activator, and LPA itself in ovarian cancer cells, but not in normal ovarian surface epithelial cells. PSP24 and members of the endothelial
differentiation gene (EDG) family (EDG1, EDG2, EDG4, and EDG7) of G protein-coupled receptors mediate LPA signaling. Ovarian cancer cell lines do
not express EDG1 mRNA, have variable EDG2 mRNA and protein levels, and frequently exhibit levels of EDG4 mRNA and protein, suggesting that EDG4 may contribute to the deleterious effects of LPA in ovarian cancer. In contrast,
activation of the EDG2 LPA receptor on ovarian cancer cells may lead to
apoptosis and counter the effects of other LPA receptors.
|
|
Mutations |
1 mutations
Species: mouse
Mutation name: None
type: targeted overexpression
fertility: fertile
Comment: The lipid growth factor lysophosphatidic acid (LPA) is produced by ovarian cancer cells in quantities sufficient to attain concentrations of up to 10 microM. An autocrine circuit was demonstrated when ovarian cancer cells, but not normal ovarian surface epithelial cells, were proven to express LPA(2) (Edg-4) and LPA(3) (Edg-7) G protein-coupled receptors for LPA. Human LPA(2) now has been expressed transgenically in C57BL/6 mouse ovaries under direction of the alpha-inhibin large promoter Huang MC, et al
. Human LPA(2) mRNA and protein were detected in all transgenic (TG) mouse ovaries at levels far higher than in other tissues and at least fivefold higher than in cultured lines of human ovarian cancer cells, with the expected sex cord-stromal distribution. Most LPA(2) TG ovaries produced significantly higher levels than non-TG ovaries of type A, but not type B, vascular endothelial growth factor (VEGF), isomers of VEGF-A, and urokinase-type plasminogen activator (uPA). Many LPA(2) TG ovaries had elevated expression of VEGF receptors 1 and 2, and a depressed level of type 2 PA inhibitor. Thus, the LPA-LPA(2) circuit regulates ovarian cells both directly and through increases in protein growth factor systems.
|