Single amino acid (arginine) deprivation induces G1 arrest associated with inhibition of cdk4 expression in cultured human diploid fibroblasts.
Withdrawal of a single amino acid (arginine) from freely cycling early passage primary human fibroblasts caused a halt to proliferation, characterized by an accumulation of cells in the G1 phase of the cell cycle. This arrest was accompanied by the suppression of cyclin D1- and cyclin E-associated kinase activities and the appearance of hypophosphorylated retinoblastoma protein. Arginine-deprived cells remained viable for in excess of 4 days and could be made to synchronously reenter the cell cycle by restoration of the amino acid, with kinetics characteristic of exit from a quiescent state. Stimulation of cells arrested by serum withdrawal did not result in S-phase entry when arginine was omitted from the culture medium. Although cyclin D1 accumulated on normal schedule, cdk4, which increased following restimulation in amino acid-replete medium, was not induced when arginine was absent. These results suggest that arginine deprivation-in common with other "suboptimal" conditions-inhibits the passage of normal human cells through the restriction point and implicate cdk4 as the key regulatory element in amino acid-sensitive cell cycle control.
Lamb
J
J
Department of Cell Pathology, University of Aberdeen, MacRobert Building, 581 King Street, Aberdeen, AB24 5UA, Scotland, United Kingdom.
Wheatley
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DN
D019943:Amino Acid Substitution; D001120:Arginine; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D016193:G1 Phase; D005786:Gene Expression Regulation; D006801:Humans; D011518:Proto-Oncogene Proteins; D013329:Structure-Activity Relationship
D011518:Proto-Oncogene Proteins; D001120:Arginine; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases