Growth and Cell Cycle Abnormalities of Fibroblasts From Tangier Disease Patients

摘要: We have investigated the abnormal proliferation and morphology of fibroblasts from patients with Tangier disease (TD), a high density lipoprotein (HDL) deficiency syndrome that is characterized by impairment HDL3-mediated lipid efflux Gi-protein-mediated signaling via phosphatidylinositol-specific phospholipase C (PI-PLC) D (PLD). TD displayed 30% to 50% reduced in vitro growth rate 1.6-fold increased cell surface area. The response different mitogens was diminished, asynchronously growing showed 4.4+/-0.3% S-phase 19.1+/-0.5% G2/M-phase cells compared 9.7+/-0.6% 7.8+/-0.5%, respectively, controls. Monensin, but not brefeldin A, induced an S- distribution control similar found fibroblasts. This effect monensin accompanied increase ceramide levels controls, whereas already had 2.5-fold basal concentration. Incubation C2 threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) mimicked on cycle. inhibition neither Gi protein function pertussis toxin nor PLD butanol resulted arrest. Propranolol, known phosphatidic acid levels, ineffective reversing arrest In addition, cDNA sequences mRNA expression participants PI-PLC or signaling, ie, G-protein subunits alphai1, alphai2, alphai3; phosphatidylinositol transfer proteins-alpha -beta; ADP ribosylation factors 1 3 were be normal. Thus, cycle abnormalities are likely related impaired Golgi sphingolipid rather than inoperative signal transduction. Because PDMP also decrease fibroblasts, pathways seem involved disturbances transport retardation.