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Proc Natl Acad Sci U S A. Jun 7, 1994; 91(12): 5490–5494.
PMCID: PMC44021

Structure and cell cycle-regulated transcription of the human cyclin A gene.

Abstract

Cyclin A is a cell cycle regulatory protein that functions in mitotic and S-phase control in mammalian somatic cells. Its deregulated expression may have a role in cellular transformation. We have cloned and sequenced the human cyclin A gene and cDNAs representing its mRNAs and have characterized its promoter. Using synchronized cultures of NIH 3T3 cells stably transfected with cyclin A promoter/luciferase constructs, we show that the promoter is repressed during the G1 phase of the cell cycle and is activated at S-phase entry. Cell cycle regulation of the cyclin A gene promoter is mediated by sequences extending from -79 to +100 relative to the predominant transcription start site. It does not require the presence of a functional retinoblastoma protein.

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  • Pines J. Cyclins and cyclin-dependent kinases: take your partners. Trends Biochem Sci. 1993 Jun;18(6):195–197. [PubMed]
  • Sherr CJ. Mammalian G1 cyclins. Cell. 1993 Jun 18;73(6):1059–1065. [PubMed]
  • Pagano M, Pepperkok R, Verde F, Ansorge W, Draetta G. Cyclin A is required at two points in the human cell cycle. EMBO J. 1992 Mar;11(3):961–971. [PMC free article] [PubMed]
  • Nurse P. Universal control mechanism regulating onset of M-phase. Nature. 1990 Apr 5;344(6266):503–508. [PubMed]
  • Evans T, Rosenthal ET, Youngblom J, Distel D, Hunt T. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell. 1983 Jun;33(2):389–396. [PubMed]
  • Pines J, Hunter T. Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B. Nature. 1990 Aug 23;346(6286):760–763. [PubMed]
  • Tsai LH, Harlow E, Meyerson M. Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase. Nature. 1991 Sep 12;353(6340):174–177. [PubMed]
  • Swenson KI, Farrell KM, Ruderman JV. The clam embryo protein cyclin A induces entry into M phase and the resumption of meiosis in Xenopus oocytes. Cell. 1986 Dec 26;47(6):861–870. [PubMed]
  • Luca FC, Shibuya EK, Dohrmann CE, Ruderman JV. Both cyclin A delta 60 and B delta 97 are stable and arrest cells in M-phase, but only cyclin B delta 97 turns on cyclin destruction. EMBO J. 1991 Dec;10(13):4311–4320. [PMC free article] [PubMed]
  • Lehner CF, O'Farrell PH. The roles of Drosophila cyclins A and B in mitotic control. Cell. 1990 May 4;61(3):535–547. [PMC free article] [PubMed]
  • Walker DH, Maller JL. Role for cyclin A in the dependence of mitosis on completion of DNA replication. Nature. 1991 Nov 28;354(6351):314–317. [PubMed]
  • Zindy F, Lamas E, Chenivesse X, Sobczak J, Wang J, Fesquet D, Henglein B, Bréchot C. Cyclin A is required in S phase in normal epithelial cells. Biochem Biophys Res Commun. 1992 Feb 14;182(3):1144–1154. [PubMed]
  • Girard F, Strausfeld U, Fernandez A, Lamb NJ. Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell. 1991 Dec 20;67(6):1169–1179. [PubMed]
  • Sobczak-Thepot J, Harper F, Florentin Y, Zindy F, Brechot C, Puvion E. Localization of cyclin A at the sites of cellular DNA replication. Exp Cell Res. 1993 May;206(1):43–48. [PubMed]
  • Cardoso MC, Leonhardt H, Nadal-Ginard B. Reversal of terminal differentiation and control of DNA replication: cyclin A and Cdk2 specifically localize at subnuclear sites of DNA replication. Cell. 1993 Sep 24;74(6):979–992. [PubMed]
  • D'Urso G, Marraccino RL, Marshak DR, Roberts JM. Cell cycle control of DNA replication by a homologue from human cells of the p34cdc2 protein kinase. Science. 1990 Nov 9;250(4982):786–791. [PubMed]
  • Dutta A, Stillman B. cdc2 family kinases phosphorylate a human cell DNA replication factor, RPA, and activate DNA replication. EMBO J. 1992 Jun;11(6):2189–2199. [PMC free article] [PubMed]
  • Elledge SJ, Richman R, Hall FL, Williams RT, Lodgson N, Harper JW. CDK2 encodes a 33-kDa cyclin A-associated protein kinase and is expressed before CDC2 in the cell cycle. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2907–2911. [PMC free article] [PubMed]
  • Shirodkar S, Ewen M, DeCaprio JA, Morgan J, Livingston DM, Chittenden T. The transcription factor E2F interacts with the retinoblastoma product and a p107-cyclin A complex in a cell cycle-regulated manner. Cell. 1992 Jan 10;68(1):157–166. [PubMed]
  • Devoto SH, Mudryj M, Pines J, Hunter T, Nevins JR. A cyclin A-protein kinase complex possesses sequence-specific DNA binding activity: p33cdk2 is a component of the E2F-cyclin A complex. Cell. 1992 Jan 10;68(1):167–176. [PubMed]
  • Mudryj M, Hiebert SW, Nevins JR. A role for the adenovirus inducible E2F transcription factor in a proliferation dependent signal transduction pathway. EMBO J. 1990 Jul;9(7):2179–2184. [PMC free article] [PubMed]
  • Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR. The E2F transcription factor is a cellular target for the RB protein. Cell. 1991 Jun 14;65(6):1053–1061. [PubMed]
  • Bandara LR, La Thangue NB. Adenovirus E1a prevents the retinoblastoma gene product from complexing with a cellular transcription factor. Nature. 1991 Jun 6;351(6326):494–497. [PubMed]
  • Bagchi S, Raychaudhuri P, Nevins JR. Adenovirus E1A proteins can dissociate heteromeric complexes involving the E2F transcription factor: a novel mechanism for E1A trans-activation. Cell. 1990 Aug 24;62(4):659–669. [PubMed]
  • Ewen ME, Faha B, Harlow E, Livingston DM. Interaction of p107 with cyclin A independent of complex formation with viral oncoproteins. Science. 1992 Jan 3;255(5040):85–87. [PubMed]
  • Giordano A, Whyte P, Harlow E, Franza BR, Jr, Beach D, Draetta G. A 60 kd cdc2-associated polypeptide complexes with the E1A proteins in adenovirus-infected cells. Cell. 1989 Sep 8;58(5):981–990. [PubMed]
  • Wang J, Chenivesse X, Henglein B, Bréchot C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature. 1990 Feb 8;343(6258):555–557. [PubMed]
  • Wang J, Zindy F, Chenivesse X, Lamas E, Henglein B, Bréchot C. Modification of cyclin A expression by hepatitis B virus DNA integration in a hepatocellular carcinoma. Oncogene. 1992 Aug;7(8):1653–1656. [PubMed]
  • Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 1993 May;7(5):812–821. [PubMed]
  • Lucibello FC, Sewing A, Brüsselbach S, Bürger C, Müller R. Deregulation of cyclins D1 and E and suppression of cdk2 and cdk4 in senescent human fibroblasts. J Cell Sci. 1993 May;105(Pt 1):123–133. [PubMed]
  • Sewing A, Bürger C, Brüsselbach S, Schalk C, Lucibello FC, Müller R. Human cyclin D1 encodes a labile nuclear protein whose synthesis is directly induced by growth factors and suppressed by cyclic AMP. J Cell Sci. 1993 Feb;104(Pt 2):545–555. [PubMed]
  • Barlat I, Fesquet D, Bréchot C, Henglein B, Dupuy d'Angeac A, Vié A, Blanchard JM. Loss of the G1-S control of cyclin A expression during tumoral progression of Chinese hamster lung fibroblasts. Cell Growth Differ. 1993 Feb;4(2):105–113. [PubMed]
  • Eick D. Elongation and maturation of c-myc RNA is inhibited by differentiation inducing agents in HL60 cells. Nucleic Acids Res. 1990 Mar 11;18(5):1199–1205. [PMC free article] [PubMed]
  • de Wet JR, Wood KV, DeLuca M, Helinski DR, Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. [PMC free article] [PubMed]
  • Graham FL, van der Eb AJ. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. [PubMed]
  • Rosenthal N. Identification of regulatory elements of cloned genes with functional assays. Methods Enzymol. 1987;152:704–720. [PubMed]
  • Scheffner M, Münger K, Byrne JC, Howley PM. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5523–5527. [PMC free article] [PubMed]
  • Glotzer M, Murray AW, Kirschner MW. Cyclin is degraded by the ubiquitin pathway. Nature. 1991 Jan 10;349(6305):132–138. [PubMed]
  • Shaw G, Kamen R. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986 Aug 29;46(5):659–667. [PubMed]
  • Lehner CF, O'Farrell PH. Expression and function of Drosophila cyclin A during embryonic cell cycle progression. Cell. 1989 Mar 24;56(6):957–968. [PMC free article] [PubMed]
  • Jones NC, Rigby PW, Ziff EB. Trans-acting protein factors and the regulation of eukaryotic transcription: lessons from studies on DNA tumor viruses. Genes Dev. 1988 Mar;2(3):267–281. [PubMed]
  • Kadonaga JT, Tjian R. Affinity purification of sequence-specific DNA binding proteins. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5889–5893. [PMC free article] [PubMed]
  • Lee KA, Hai TY, SivaRaman L, Thimmappaya B, Hurst HC, Jones NC, Green MR. A cellular protein, activating transcription factor, activates transcription of multiple E1A-inducible adenovirus early promoters. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8355–8359. [PMC free article] [PubMed]
  • Dou QP, Fridovich-Keil JL, Pardee AB. Inducible proteins binding to the murine thymidine kinase promoter in late G1/S phase. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1157–1161. [PMC free article] [PubMed]
  • Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrlich P, Karin M. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell. 1987 Jun 19;49(6):729–739. [PubMed]
  • Kern SE, Kinzler KW, Bruskin A, Jarosz D, Friedman P, Prives C, Vogelstein B. Identification of p53 as a sequence-specific DNA-binding protein. Science. 1991 Jun 21;252(5013):1708–1711. [PubMed]
  • Anderson GM, Freytag SO. Synergistic activation of a human promoter in vivo by transcription factor Sp1. Mol Cell Biol. 1991 Apr;11(4):1935–1943. [PMC free article] [PubMed]
  • Howe PH, Draetta G, Leof EB. Transforming growth factor beta 1 inhibition of p34cdc2 phosphorylation and histone H1 kinase activity is associated with G1/S-phase growth arrest. Mol Cell Biol. 1991 Mar;11(3):1185–1194. [PMC free article] [PubMed]
  • Morris GF, Mathews MB. Analysis of the proliferating cell nuclear antigen promoter and its response to adenovirus early region 1. J Biol Chem. 1990 Sep 25;265(27):16116–16125. [PubMed]
  • Motokura T, Arnold A. PRAD1/cyclin D1 proto-oncogene: genomic organization, 5' DNA sequence, and sequence of a tumor-specific rearrangement breakpoint. Genes Chromosomes Cancer. 1993 Jun;7(2):89–95. [PubMed]
  • Zhu L, van den Heuvel S, Helin K, Fattaey A, Ewen M, Livingston D, Dyson N, Harlow E. Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein. Genes Dev. 1993 Jul;7(7A):1111–1125. [PubMed]
  • Dou QP, Markell PJ, Pardee AB. Thymidine kinase transcription is regulated at G1/S phase by a complex that contains retinoblastoma-like protein and a cdc2 kinase. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3256–3260. [PMC free article] [PubMed]
  • Means AL, Slansky JE, McMahon SL, Knuth MW, Farnham PJ. The HIP1 binding site is required for growth regulation of the dihydrofolate reductase gene promoter. Mol Cell Biol. 1992 Mar;12(3):1054–1063. [PMC free article] [PubMed]
  • Lam EW, Watson RJ. An E2F-binding site mediates cell-cycle regulated repression of mouse B-myb transcription. EMBO J. 1993 Jul;12(7):2705–2713. [PMC free article] [PubMed]
  • Burggraf S, Larsen N, Woese CR, Stetter KO. An intron within the 16S ribosomal RNA gene of the archaeon Pyrobaculum aerophilum. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2547–2550. [PMC free article] [PubMed]
  • Laiho M, DeCaprio JA, Ludlow JW, Livingston DM, Massagué J. Growth inhibition by TGF-beta linked to suppression of retinoblastoma protein phosphorylation. Cell. 1990 Jul 13;62(1):175–185. [PubMed]

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