Transcription Factors

Post-translational modifications and subcellular localizations modulate transcription factors, generating a code that is deciphered into an activity. We describe our current understanding of these processes for Ets factors, which have recently been recognized for their importance in various biological processes. We present the global picture for the family, and then focus on particular aspects related to cancer and hypoxia. The analysis of Post-translational modification and cellular localization is only beginning to enter the age of “omic,” high content, systems biology. Our snap-shots of particularly active fields point to the directions in which new techniques will be needed, in our search for a more complete description of regulatory pathways.

[1]  J. Ihle.  The Stat family in cytokine signaling. , 2001, Current opinion in cell biology.

[2]  D. Levy,et al.  Targeted Disruption of the Mouse Stat1 Gene Results in Compromised Innate Immunity to Viral Disease , 1996, Cell.

[3]  Yuichi Makino,et al.  Regulation of the Hypoxia-inducible Transcription Factor 1α by the Ubiquitin-Proteasome Pathway* , 1999, The Journal of Biological Chemistry.

[4]  B. Chait,et al.  DNA binding of in vitro activated Stat1 alpha, Stat1 beta and truncated Stat1: interaction between NH2‐terminal domains stabilizes binding of two dimers to tandem DNA sites. , 1996, The EMBO journal.

[5]  J. Gutkind,et al.  MAPK and Akt act cooperatively but independently on hypoxia inducible factor-1alpha in rasV12 upregulation of VEGF. , 2001, Biochemical and biophysical research communications.

[6]  S. John,et al.  Regulation of STAT signalling by proteolytic processing. , 2004, European journal of biochemistry.

[7]  U. Vinkemeier,et al.  Nucleocytoplasmic translocation of Stat1 is regulated by a leucine-rich export signal in the coiled-coil domain. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[8]  R. Schreiber,et al.  Stat recruitment by tyrosine-phosphorylated cytokine receptors: an ordered reversible affinity-driven process. , 1995, Immunity.

[9]  B. Brüne,et al.  HIF‐1α protein as a target for S‐nitrosation , 2003, FEBS letters.

[10]  Edward Yang,et al.  Dissociation Time from DNA Determines Transcriptional Function in a STAT1 Linker Mutant* , 2002, The Journal of Biological Chemistry.

[11]  L. Kinnunen,et al.  Arginine/Lysine-rich Nuclear Localization Signals Mediate Interactions between Dimeric STATs and Importin α5* , 2002, The Journal of Biological Chemistry.

[12]  J. Darnell,et al.  Crystal Structure of a Tyrosine Phosphorylated STAT-1 Dimer Bound to DNA , 1998, Cell.

[13]  J. Darnell.  STATs and gene regulation. , 1997, Science.

[14]  E. Yang,et al.  Modulation of p300 binding by posttranslational modifications of the C‐terminal activation domain of hypoxia‐inducible factor‐1α , 2007, FEBS letters.

[15]  M. Ashcroft,et al.  Growth Factor-Mediated Induction of HDM2 Positively Regulates Hypoxia-Inducible Factor 1α Expression , 2004, Molecular and Cellular Biology.

[16]  J. Pouysségur,et al.  Arrest-defective-1 Protein, an Acetyltransferase, Does Not Alter Stability of Hypoxia-inducible Factor (HIF)-1α and Is Not Induced by Hypoxia or HIF* , 2005, Journal of Biological Chemistry.

[17]  D. Newmeyer,et al.  Inhibition of in vitro nuclear transport by a lectin that binds to nuclear pores , 1987, The Journal of cell biology.

[18]  H. Hauser,et al.  Dynamic redistribution of STAT1 protein in IFN signaling visualized by GFP fusion proteins. , 1999, European journal of biochemistry.

[19]  J. Darnell,et al.  Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions , 1994, Cell.

[20]  T. Kietzmann,et al.  Induction of plasminogen activator inhibitor I gene expression by intracellular calcium via hypoxia-inducible factor-1. , 2004, Blood.

[21]  Michael I. Wilson,et al.  Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation , 2001, Science.

[22]  C. Wykoff,et al.  The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis , 1999, Nature.

[23]  K. Kivirikko,et al.  Posttranslational enzymes in the biosynthesis of collagen: intracellular enzymes. , 1982, Methods in enzymology.

[24]  D. Peet,et al.  FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. , 2002, Genes & development.

[25]  N. Sang,et al.  MAPK Signaling Up-regulates the Activity of Hypoxia-inducible Factors by Its Effects on p300* , 2003, The Journal of Biological Chemistry.

[26]  M. Yanagida,et al.  Leptomycin B inhibition of signal-mediated nuclear export by direct binding to CRM1. , 1998, Experimental cell research.

[27]  E. Hur,et al.  Mitogen-activated protein kinase kinase inhibitor PD98059 blocks the trans-activation but not the stabilization or DNA binding ability of hypoxia-inducible factor-1alpha. , 2001 .

[28]  S. Adam,et al.  Nuclear protein import in permeabilized mammalian cells requires soluble cytoplasmic factors , 1990, The Journal of cell biology.

[29]  K. Kivirikko,et al.  An Endoplasmic Reticulum Transmembrane Prolyl 4-Hydroxylase Is Induced by Hypoxia and Acts on Hypoxia-inducible Factor α* , 2007, Journal of Biological Chemistry.

[30]  K. Kivirikko,et al.  The Length of Peptide Substrates Has a Marked Effect on Hydroxylation by the Hypoxia-inducible Factor Prolyl 4-Hydroxylases* , 2006, Journal of Biological Chemistry.

[31]  J. Darnell,et al.  Signalling: STATs: transcriptional control and biological impact , 2002, Nature Reviews Molecular Cell Biology.

[32]  I. Kerr,et al.  STAT1 from the cell membrane to the DNA , 2001, The EMBO journal.

[33]  J. Caro,et al.  Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. , 1997, The Journal of biological chemistry.

[34]  M. Ivan,et al.  Structure of an HIF-1α-pVHL Complex: Hydroxyproline Recognition in Signaling , 2002, Science.

[35]  Christine C. Hudson,et al.  Regulation of Hypoxia-Inducible Factor 1α Expression and Function by the Mammalian Target of Rapamycin , 2002, Molecular and Cellular Biology.

[36]  R. Evjenth,et al.  Interaction between HIF-1 alpha (ODD) and hARD1 does not induce acetylation and destabilization of HIF-1 alpha. , 2005, FEBS letters.

[37]  B. Brüne,et al.  Regulation of the hypoxia-inducible factor 1alpha by the inflammatory mediators nitric oxide and tumor necrosis factor-alpha in contrast to desferroxamine and phenylarsine oxide. , 2001, The Journal of biological chemistry.

[38]  Hansjörg Hauser,et al.  Nucleocytoplasmic shuttling revealed by FRAP and FLIP technologies. , 2005, Current opinion in biotechnology.

[39]  G. Semenza,et al.  Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. , 2000, Cancer research.

[40]  J E Darnell,et al.  A nuclear protein tyrosine phosphatase is required for the inactivation of Stat1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[41]  U. Vinkemeier,et al.  Green fluorescent protein‐tagging reduces the nucleocytoplasmic shuttling specifically of unphosphorylated STAT1 , 2007, The FEBS journal.

[42]  D. Mottet,et al.  Regulation of Hypoxia-inducible Factor-1α Protein Level during Hypoxic Conditions by the Phosphatidylinositol 3-Kinase/Akt/Glycogen Synthase Kinase 3β Pathway in HepG2 Cells* , 2003, Journal of Biological Chemistry.

[43]  Y. M. Lee,et al.  Jab1 interacts directly with HIF-1alpha and regulates its stability. , 2002, The Journal of biological chemistry.

[44]  G. Semenza.  Signal transduction to hypoxia-inducible factor 1. , 2002, Biochemical pharmacology.

[45]  T. Decker,et al.  GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. , 1997, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[46]  F. Holsboer,et al.  RSUME, a Small RWD-Containing Protein, Enhances SUMO Conjugation and Stabilizes HIF-1α during Hypoxia , 2007, Cell.

[47]  Yu-Rong Fu,et al.  Identification of a Nuclear Stat 1 Protein Tyrosine Phosphatase , 2002 .

[48]  U. Vinkemeier,et al.  A Single Residue Modulates Tyrosine Dephosphorylation, Oligomerization, and Nuclear Accumulation of Stat Transcription Factors* , 2004, Journal of Biological Chemistry.

[49]  J. Darnell,et al.  Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein. , 1992, Science.

[50]  P. Sehgal.  Paradigm shifts in the cell biology of STAT signaling. , 2008, Seminars in cell & developmental biology.

[51]  Andreas Marg,et al.  DNA binding controls inactivation and nuclear accumulation of the transcription factor Stat1. , 2003, Genes & development.

[52]  I. Lödige,et al.  Constitutive and IFN‐γ‐induced nuclear import of STAT1 proceed through independent pathways , 2002 .

[53]  J. Darnell,et al.  Maximal activation of transcription by statl and stat3 requires both tyrosine and serine phosphorylation , 1995, Cell.

[54]  E. Cummins,et al.  c-Jun NH2-Terminal Kinase Activation Contributes to Hypoxia-Inducible Factor 1α–Dependent P-Glycoprotein Expression in Hypoxia , 2004, Cancer Research.

[55]  R. Schreiber,et al.  Targeted Disruption of the Stat1 Gene in Mice Reveals Unexpected Physiologic Specificity in the JAK–STAT Signaling Pathway , 1996, Cell.

[56]  M. Dewhirst,et al.  Regulation of HIF-1alpha stability through S-nitrosylation. , 2007, Molecular cell.

[57]  G. Semenza,et al.  FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. , 2001 .

[58]  J. Pouysségur,et al.  p42/p44 Mitogen-activated Protein Kinases Phosphorylate Hypoxia-inducible Factor 1α (HIF-1α) and Enhance the Transcriptional Activity of HIF-1* , 1999, The Journal of Biological Chemistry.

[59]  A. Koong,et al.  Loss of PTEN facilitates HIF-1-mediated gene expression. , 2000, Genes & development.

[60]  Jinke Cheng,et al.  SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. , 2007, Cell.

[61]  Christopher J Schofield,et al.  Hypoxia-inducible Factor (HIF) Asparagine Hydroxylase Is Identical to Factor Inhibiting HIF (FIH) and Is Related to the Cupin Structural Family* , 2002, The Journal of Biological Chemistry.

[62]  T. Hoey,et al.  Cooperative DNA Binding and Sequence-Selective Recognition Conferred by the STAT Amino-Terminal Domain , 1996, Science.

[63]  J. Pouysségur,et al.  ARDent about acetylation and deacetylation in hypoxia signalling. , 2006, Trends in cell biology.

[64]  E. J. Song,et al.  Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. , 2002, Cell.

[65]  M. Vigneron,et al.  Microinjected antibodies interfere with protein nucleocytoplasmic shuttling by distinct molecular mechanisms , 2008, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[66]  G. Stark,et al.  Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon‐alpha and ‐gamma signal transduction pathways. , 1993, The EMBO journal.

[67]  J. Darnell,et al.  Dephosphorylation of phosphotyrosine on STAT1 dimers requires extensive spatial reorientation of the monomers facilitated by the N-terminal domain. , 2006, Genes & development.

[68]  S. Herzig,et al.  Transcriptional regulation of plasminogen activator inhibitor-1 expression by insulin-like growth factor-1 via MAP kinases and hypoxia-inducible factor-1 in HepG2 cells , 2005, Thrombosis and Haemostasis.

[69]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[70]  K. Jungermann,et al.  Regulation of the hypoxia-dependent plasminogen activator inhibitor 1 expression by MAP kinases , 2003, Thrombosis and Haemostasis.

[71]  A. Tee,et al.  Hypoxia-inducible Factor 1α Is Regulated by the Mammalian Target of Rapamycin (mTOR) via an mTOR Signaling Motif* , 2007, Journal of Biological Chemistry.

[72]  L. Poellinger,et al.  Mechanism of regulation of the hypoxia‐inducible factor‐1α by the von Hippel‐Lindau tumor suppressor protein , 2000, The EMBO journal.

[73]  J. Gordon.  Use of vanadate as protein-phosphotyrosine phosphatase inhibitor. , 1991, Methods in enzymology.

[74]  J. Fandrey,et al.  Nitric Oxide Modulates Oxygen Sensing by Hypoxia-inducible Factor 1-dependent Induction of Prolyl Hydroxylase 2* , 2007, Journal of Biological Chemistry.

[75]  J. Bromberg,et al.  STAT proteins: signal tranducers and activators of transcription. , 2001, Methods in enzymology.

[76]  G. Panayotou,et al.  Identification of MAPK Phosphorylation Sites and Their Role in the Localization and Activity of Hypoxia-inducible Factor-1α* , 2006, Journal of Biological Chemistry.

[77]  A. Brivanlou,et al.  Signal Transduction and the Control of Gene Expression , 2002, Science.

[78]  U. Vinkemeier,et al.  Ratjadone and leptomycin B block CRM1‐dependent nuclear export by identical mechanisms , 2004, FEBS letters.

[79]  Andreas Marg,et al.  Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and CRM1-dependent nuclear export control the subcellular distribution of latent Stat1 , 2004, The Journal of cell biology.

[80]  Kyu-Won Kim,et al.  Sumoylation increases HIF-1alpha stability and its transcriptional activity. , 2004, Biochemical and biophysical research communications.

[81]  W. Webb,et al.  Mobility measurement by analysis of fluorescence photobleaching recovery kinetics. , 1976, Biophysical journal.

[82]  J. Darnell,et al.  A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. , 1995, Genes & development.

[83]  J. Darnell,et al.  The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase. , 1996, The EMBO journal.

[84]  Kevin M. McBride,et al.  Regulated nuclear import of the STAT1 transcription factor by direct binding of importin‐α , 2002, The EMBO journal.

[85]  E. Paraskeva,et al.  Atypical CRM1-dependent Nuclear Export Signal Mediates Regulation of Hypoxia-inducible Factor-1α by MAPK* , 2008, Journal of Biological Chemistry.

[86]  R. Corriveau,et al.  An Evolutionarily Conserved N-terminal Acetyltransferase Complex Associated with Neuronal Development* , 2003, Journal of Biological Chemistry.

[87]  R. Johns,et al.  Normoxic stabilization of hypoxia-inducible factor-1 expression and activity: redox-dependent effect of nitrogen oxides. , 2000, Molecular pharmacology.

[88]  B. Brüne,et al.  Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases. , 2003, Molecular biology of the cell.

[89]  M. Ivan,et al.  Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein , 2000, Nature Cell Biology.

[90]  T. Hunter,et al.  Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. , 2001, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[91]  P. Bucher,et al.  DNA Binding Specificity of Different STAT Proteins , 2001, The Journal of Biological Chemistry.

[92]  G. Semenza,et al.  Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. , 2000, Genes & development.

[93]  Denis Mottet,et al.  Transduction pathways involved in Hypoxia-Inducible Factor-1 phosphorylation and activation. , 2001, Free radical biology & medicine.

[94]  J. Darnell,et al.  Interactions between STAT and non-STAT proteins in the interferon-stimulated gene factor 3 transcription complex , 1996, Molecular and cellular biology.

[95]  J. Darnell,et al.  A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. , 1993, Science.

[96]  D. Peet,et al.  Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch , 2002, Science.

[97]  K. Baringhaus,et al.  Inhibition of prolyl 4-hydroxylase by oxalyl amino acid derivatives in vitro, in isolated microsomes and in embryonic chicken tissues. , 1994, The Biochemical journal.

[98]  P. Ratcliffe,et al.  Independent function of two destruction domains in hypoxia‐inducible factor‐α chains activated by prolyl hydroxylation , 2001, The EMBO journal.

[99]  M. Tremblay,et al.  The T-cell protein tyrosine phosphatase. , 2000, Seminars in immunology.

[100]  J. Pouysségur,et al.  SUMOylation of hypoxia-inducible factor-1alpha reduces its transcriptional activity. , 2007, Biochemical and biophysical research communications.

[101]  J. Darnell,et al.  Implications of an antiparallel dimeric structure of nonphosphorylated STAT1 for the activation-inactivation cycle. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[102]  T. Kietzmann,et al.  Glycogen Synthase Kinase 3 Phosphorylates Hypoxia-Inducible Factor 1α and Mediates Its Destabilization in a VHL-Independent Manner , 2007, Molecular and Cellular Biology.