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Proc Natl Acad Sci U S A. Jul 23, 1996; 93(15): 7673–7678.
PMCID: PMC38805

Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma.

Abstract

Type I (alpha, beta) and type II (gamma) interferons (IFNs) can restrict the growth of many cell types. INF-stimulated gene transcription, a key early event in IFN response, acts through the Janus kinase-signal transducers and activators of transcription pathway, in which both IFN-alpha and IFN-gamma activate the transcription factor Stat1. A cell line lacking Stat1 (U3A) was not growth-arrested by IFN-alpha or IFN-gamma, and experiments were carried out with U3A cells permanently expressing normal or various mutant forms of Stat1 protein. Only cells in which complete Stat1 activity was available (Stat1alpha) were growth-inhibited by IFN-gamma. A mutant that supports 20-30% normal transcription did not cause growth restraint. In contrast, IFN-alpha growth restraint was imposed by cells producing Stat1beta, which lacks transcriptional activation potential. This parallels earlier results showing the truncated Stat1 can function in IFN-alpha gene activation. In addition to experiments on long-term cultured cells, we also found that wild-type primary mouse embryonic fibroblasts were inhibited by IFNs, but fibroblasts from Stat1-deficient mouse embryos were not inhibited by IFNs.

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  • Weinberg RA. The molecular basis of oncogenes and tumor suppressor genes. Ann N Y Acad Sci. 1995 Jun 30;758:331–338. [PubMed]
  • Lin SL, Kikuchi T, Pledger WJ, Tamm I. Interferon inhibits the establishment of competence in Go/S-phase transition. Science. 1986 Jul 18;233(4761):356–359. [PubMed]
  • Balkwill F, Taylor-Papadimitriou J. Interferon affects both G1 and S+G2 in cells stimulated from quiescence to growth. Nature. 1978 Aug 24;274(5673):798–800. [PubMed]
  • Balkwill FR, Oliver RT. Growth inhibitory effects of interferon on normal and malignant human haemopoietic cells. Int J Cancer. 1977 Oct 15;20(4):500–505. [PubMed]
  • Fu XY, Kessler DS, Veals SA, Levy DE, Darnell JE., Jr ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8555–8559. [PMC free article] [PubMed]
  • Fu XY, Schindler C, Improta T, Aebersold R, Darnell JE., Jr The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7840–7843. [PMC free article] [PubMed]
  • Schindler C, Fu XY, Improta T, Aebersold R, Darnell JE., Jr Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7836–7839. [PMC free article] [PubMed]
  • Shuai K, Schindler C, Prezioso VR, Darnell JE., Jr Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein. Science. 1992 Dec 11;258(5089):1808–1812. [PubMed]
  • Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE., Jr Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell. 1994 Mar 11;76(5):821–828. [PubMed]
  • Darnell JE, Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. [PubMed]
  • Müller M, Laxton C, Briscoe J, Schindler C, Improta T, Darnell JE, Jr, Stark GR, Kerr IM. Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon-alpha and -gamma signal transduction pathways. EMBO J. 1993 Nov;12(11):4221–4228. [PMC free article] [PubMed]
  • Shuai K, Ziemiecki A, Wilks AF, Harpur AG, Sadowski HB, Gilman MZ, Darnell JE. Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Nature. 1993 Dec 9;366(6455):580–583. [PubMed]
  • Yan R, Qureshi S, Zhong Z, Wen Z, Darnell JE., Jr The genomic structure of the STAT genes: multiple exons in coincident sites in Stat1 and Stat2. Nucleic Acids Res. 1995 Feb 11;23(3):459–463. [PMC free article] [PubMed]
  • Qureshi SA, Leung S, Kerr IM, Stark GR, Darnell JE., Jr Function of Stat2 protein in transcriptional activation by alpha interferon. Mol Cell Biol. 1996 Jan;16(1):288–293. [PMC free article] [PubMed]
  • Zhong Z, Wen Z, Darnell JE., Jr Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994 Apr 1;264(5155):95–98. [PubMed]
  • Zhong Z, Wen Z, Darnell JE., Jr Stat3 and Stat4: members of the family of signal transducers and activators of transcription. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4806–4810. [PMC free article] [PubMed]
  • Wakao H, Gouilleux F, Groner B. Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. EMBO J. 1994 May 1;13(9):2182–2191. [PMC free article] [PubMed]
  • Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL. An interleukin-4-induced transcription factor: IL-4 Stat. Science. 1994 Sep 16;265(5179):1701–1706. [PubMed]
  • Schindler C, Darnell JE., Jr Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu Rev Biochem. 1995;64:621–651. [PubMed]
  • Horvath CM, Wen Z, Darnell JE., Jr A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. Genes Dev. 1995 Apr 15;9(8):984–994. [PubMed]
  • Wen Z, Zhong Z, Darnell JE., Jr Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995 Jul 28;82(2):241–250. [PubMed]
  • Improta T, Schindler C, Horvath CM, Kerr IM, Stark GR, Darnell JE., Jr Transcription factor ISGF-3 formation requires phosphorylated Stat91 protein, but Stat113 protein is phosphorylated independently of Stat91 protein. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4776–4780. [PMC free article] [PubMed]
  • Shuai K, Stark GR, Kerr IM, Darnell JE., Jr A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science. 1993 Sep 24;261(5129):1744–1746. [PubMed]
  • Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS, Kaplan DH, Riley JK, Greenlund AC, Campbell D, et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell. 1996 Feb 9;84(3):431–442. [PubMed]
  • Fan Z, Lu Y, Wu X, DeBlasio A, Koff A, Mendelsohn J. Prolonged induction of p21Cip1/WAF1/CDK2/PCNA complex by epidermal growth factor receptor activation mediates ligand-induced A431 cell growth inhibition. J Cell Biol. 1995 Oct;131(1):235–242. [PMC free article] [PubMed]
  • McKendry R, John J, Flavell D, Müller M, Kerr IM, Stark GR. High-frequency mutagenesis of human cells and characterization of a mutant unresponsive to both alpha and gamma interferons. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11455–11459. [PMC free article] [PubMed]
  • Pellegrini S, John J, Shearer M, Kerr IM, Stark GR. Use of a selectable marker regulated by alpha interferon to obtain mutations in the signaling pathway. Mol Cell Biol. 1989 Nov;9(11):4605–4612. [PMC free article] [PubMed]
  • Shuai K, Ziemiecki A, Wilks AF, Harpur AG, Sadowski HB, Gilman MZ, Darnell JE. Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Nature. 1993 Dec 9;366(6455):580–583. [PubMed]
  • Horvath CM, Darnell JE., Jr The antiviral state induced by alpha interferon and gamma interferon requires transcriptionally active Stat1 protein. J Virol. 1996 Jan;70(1):647–650. [PMC free article] [PubMed]
  • Qureshi SA, Salditt-Georgieff M, Darnell JE., Jr Tyrosine-phosphorylated Stat1 and Stat2 plus a 48-kDa protein all contact DNA in forming interferon-stimulated-gene factor 3. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3829–3833. [PMC free article] [PubMed]
  • Seidel HM, Milocco LH, Lamb P, Darnell JE, Jr, Stein RB, Rosen J. Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):3041–3045. [PMC free article] [PubMed]
  • Sherr CJ. Mammalian G1 cyclins. Cell. 1993 Jun 18;73(6):1059–1065. [PubMed]
  • Kimchi A. Cytokine triggered molecular pathways that control cell cycle arrest. J Cell Biochem. 1992 Sep;50(1):1–9. [PubMed]
  • el-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994 Mar 1;54(5):1169–1174. [PubMed]
  • Gu Y, Turck CW, Morgan DO. Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature. 1993 Dec 16;366(6456):707–710. [PubMed]
  • Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. [PubMed]
  • Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993 Dec 16;366(6456):701–704. [PubMed]
  • Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994 Jan;8(1):9–22. [PubMed]
  • LOCKART RZ, Jr, EAGLE H. Requirements for growth of single human cells. Science. 1959 Jan 30;129(3344):252–254. [PubMed]

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