TAILIEUCHUNG - Báo cáo Y học: Loss-of-function variants of the human melanocortin-1 receptor gene in melanoma cells define structural determinants of receptor function

Thea-melanocyte-stimulating hormone (aMSH) receptor (MC1R) is amajordeterminant ofmammalianskinandhair pigmentation. Binding ofaMSHtoMC1Rinhuman mel-anocytes stimulates cell proliferation and synthesis of pho-toprotective eumelanin pigments. Certain MC1Ralleles have been associated with increased riskof melanoma. This can be theoretically considered on two grounds. First, gain-of-function mutations may stimulate proliferation, thus promoting dysplastic lesions. | Eur. J. Biochem. 269 6133-6141 2002 FEBS 2002 doi Loss-of-function variants of the human melanocortin-1 receptor gene in melanoma cells define structural determinants of receptor function Jesus Sanchez Meis1 Concepcion Olivares Sanchez1 Ghanem Ghanem2 John Haycock3 Jose Antonio Lozano Teruel1 Jose Carlos García-Borrón1 and Celia Jimenez-Cervantes1 1 Department of Biochemistry and Molecular Biology School of Medicine University of Murcia Spain 2LOCE Free University of Brussels Brussels Belgium 3Department of Engineering Materials University of Sheffield Sheffield UK The a-melanocyte-stimulating hormone aMSH receptor MC1R is a major determinant of mammalian skin and hair pigmentation. Binding of aMSH to MC1R in human melanocytes stimulates cell proliferation and synthesis of pho-toprotective eumelanin pigments. Certain MC1R alleles have been associated with increased risk iff melanoma. This can be theoretically considered on two grounds. First gain-of-function mutations may stimulate proliferation thus promoting dysplastic lesions. Second and opposite loss-of-function mutations may decrease eumelanin contents and impair protection against the carcinogenic effects of UV light thus predisposing to skin cancers. To test these possibilities we sequenced the MC1R gene from seven human melanoma cell HMC lines and three giant congenital nevus cell GCNC cultures. Four HMC lines and two GCNC cultures contained MC1R allelic variants. These were the known loss-of-function Arg142His and Arg151Cys alleles and a new variant Leu93Arg. Moreover impaired response to a superpotent aMSH analog was demonstrated for the cell line carrying the Leu93Arg allele and for a HMC line homozygous for wild-type MC1R. Functional analysis in heterologous cells stably or transiently expressing this variant demonstrated that Leu93Arg is a loss-of-function mutation abolishing agonist binding. These results together with site-directed mutagenesis of the vicinal Glu94 .

• Báo cáo khoa học
• Report medicine
• traditional medicine
• scientific reports
• Antimicrobial
• cell structure
• genetics
• medical knowledge
• medical research
• analysis of cytoplasmic
• oxidation
• Crystal structure
• bacteria
• hemoglobin
• medicine
• cell proliferation
• breast cancer
• chemical reaction
• gastric cancer
• hormone medicine
• tumor cells
• biochemical studies
• environmental medicine