Regulation of the cell cycle in response to inhibition of mitochondrial generated energy.
Cell cycle control is regulated through the temporal action of both cyclin-dependent kinases and cyclin binding partners. Previously, we have demonstrated that low doses of oligomycin result in a cell cycle arrest of HL-60 cells in G(1) [S. Sweet, G. Singh, Accumulation of human promyelocytic leukemic (HL-60) cells at two energetic cell cycle checkpoints, Cancer Res. 55 (1995) 5164-5167]. In this study, we provide the molecular mechanisms for the observed G(1) arrest following mitochondrial ATPase inhibition. Protein expression of cyclin E and CDK2, the kinase activity of complexed cyclin E/CDK2, and protein expression of p16, p21, and p27 were all unaffected by oligomycin administration. While CDK4 levels were unchanged following oligomycin treatment, a dramatic reduction in cyclin D(1) was observed. Moreover, increased amounts of hypo-phosphorylated retinoblastoma protein (Rbp) and Rbp bound E2F were observed following mitochondrial ATP synthase inhibition. These data provide further evidence that surveillance of available energy occurs during G(1) and ATP deprivation results in cell cycle arrest via a reduction in cyclin D.
Gemin
Adam
A
Juravinski Cancer Centre, 699 Concession St., Hamilton, Ont., Canada L8V 5C2.
Sweet
Susan
S
Preston
Tom J
TJ
Singh
Gurmit
G
D000255:Adenosine Triphosphate / Q000737:chemistry; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases / Q000096:biosynthesis; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000378:metabolism; D002498:Centrifugation; D056741:Cyclin D; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000096:biosynthesis; D051357:Cyclin-Dependent Kinase 2; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D050684:E2F Transcription Factors; D016193:G1 Phase; D018922:HL-60 Cells; D006801:Humans; D047468:Immunoprecipitation; D008928:Mitochondria / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D008954:Models, Biological; D009840:Oligomycins / Q000737:chemistry; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D056741:Cyclin D; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D009840:Oligomycins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000255:Adenosine Triphosphate; D004247:DNA; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D025261:Mitochondrial Proton-Translocating ATPases