title: Density- and serum-dependent regulation of the Reck tumor suppressor in mouse embryo fibroblasts.
abstract: Reck is a membrane-anchored glycoprotein identified as a transformation suppressor. Accumulating evidence indicates that Reck negatively regulates a wide spectrum of matrix metalloproteinases and is commonly down-regulated in a variety of malignant solid tumors. Physiological cues that regulate Reck expression, however, remained unknown. In this study, we found that Reck expression was up-regulated at high cell density, low serum, or after treatment with some kinase inhibitors, such as PP2 (Src inhibitor), LY294002 (PI3-kinase inhibitor), and PF573228 (FAK inhibitor), in mouse embryo fibroblasts. Curve fitting indicated that the levels of Reck protein and Reck mRNA are quadratic in the cell density. Other factors, including serum, extracellular matrix components (type I collagen and fibronectin), the kinase inhibitors, and some of their oncogenic targets (v-Src and PIK3CA mutants), modify the shape of the quadratic curve. Comparison of these modifications implicated Src in Reck down-regulation under sparse conditions, PI3-kinase in serum-induced Reck down-regulation, and FAK in Reck down-regulation at high cell density. Fibronectin and type I collagen down-regulated Reck, supporting the role of integrin-FAK signaling in Reck down-regulation at high cell density. Our study has revealed multiple signaling pathways impinging on Reck in cultured mouse embryo fibroblasts and sets a foundation for future studies to find effective Reck inducers of potential value in cancer therapy.
authors.affiliation: Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Mamiko
authors.initials: M
authors.lastname: Hatta
authors.forename: Tomoko
authors.initials: T
authors.lastname: Matsuzaki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Morioka
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Makoto
authors.initials: M
authors.lastname: Noda
mesh_terms: D000818:Animals; D002452:Cell Count; D002867:Chromones / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D041681:NIH 3T3 Cells; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D044967:Serum / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D015854:Up-Regulation; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: C521108:6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one; C412373:AG 1879; D002867:Chromones; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D015363:Quinolones; C492025:Reck protein, mouse; D013450:Sulfones; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases