title: Enhanced epidermal growth factor, hepatocyte growth factor, and vascular endothelial growth factor expression in tuberous sclerosis complex.
abstract: Epidermal growth factor (EGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) regulate angiogenesis and cell growth in the developing brain. EGF, HGF, and VEGF modulate the activity of the mammalian target of rapamycin (mTOR) cascade, a pathway regulating cell growth that is aberrantly activated in tuberous sclerosis complex (TSC). We hypothesized that expression of EGF, HGF, VEGF, and their receptors EGFR, c-Met, and Flt-1, respectively, would be altered in TSC. We show by cDNA array and immunohistochemical analysis that EGF, EGFR, HGF, c-Met, and VEGF, but not Flt-1, mRNA, and protein expression was up-regulated in Tsc1 conditional knockout (Tsc1(GFAP)CKO) mouse cortex. Importantly, these alterations closely predicted enhanced expression of these proteins in tuber and subependymal giant cell astrocytoma (SEGA) specimens in TSC. Expression of EGF, EGFR, HGF, c-Met, and VEGF protein, as well as hypoxia inducible factor-1α, a transcription factor that regulates VEGF levels and is also modulated by mTOR cascade activity, was enhanced in SEGAs (n = 6) and tubers (n = 10) from 15 TSC patients. Enhanced expression of these growth factors and growth factor receptors in human SEGAs and tubers and in the Tsc1(GFAP)CKO mouse may account for enhanced cellular growth and proliferation in tubers and SEGAs and provides potential target molecules for therapeutic development in TSC.
authors.affiliation: PENN Epilepsy Center and Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Whitney E
authors.initials: WE
authors.lastname: Parker
authors.forename: Ksenia A
authors.initials: KA
authors.lastname: Orlova
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Heuer
authors.forename: Marianna
authors.initials: M
authors.lastname: Baybis
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.forename: Michael
authors.initials: M
authors.lastname: Frost
authors.forename: Michael
authors.initials: M
authors.lastname: Wong
authors.forename: Peter B
authors.initials: PB
authors.lastname: Crino
mesh_terms: D000818:Animals; D001921:Brain; D002540:Cerebral Cortex / Q000378:metabolism; D002648:Child; D004815:Epidermal Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D012333:RNA, Messenger; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D019893:Ribosomal Protein S6 Kinases