Transcriptional Regulation by Extracellular signals: Mechanisms and Specificity

Changes in cell behavior induced by extracellular signaling molecules such as growth factors and cytokines require execution of a complex program of transcriptional events. While the route followed by the intracellular signal from the cell membrane to its transcription factor targets can be traced in an increasing number of cases, how the specificity of the transcriptional response of the cell to different stimuli is determined is much less clear. However, it is possible to understand at least in principle how different stimuli can activate the same signal pathway yet activate different genes and how small differences in signal strength can generate qualitative differences in gene expression. In this review we shall concentrate on transcriptional responses to cell surface receptor-activated signaling pathways; however, much of our discussion is also applicable to signals induced by environmental stresses or to extracellular signals that act directly on transcription factors, such as steroid hormones. Rather than describe in detail each of the many separate pathways from receptor to transcription factor, we have attempted to compare and contrast regulation of a representative set of transcription factors. These factors are introduced in Figure 1, and their properties are summarized in Table 1. To set the stage, we briefly discuss the different properties of transcription factors that can be modified to regulate their behavior in response to signals. We then use relatively well-characterized signaling pathways to illustrate different strategies by which an extracellular stimu lus is converted to an active transcription factor in the nucleus. Finally, we use these examples to illustrate two aspects of specificity in the transcriptional response to signals: first, the means by which a given stimulus specifically targets particular transcription factors and DNA targets; and second, the means by which differential responses to qualitatively and quantitatively different signals can be generated.

[1]  R. Silverman,et al.  Blockage of NF-kappa B signaling by selective ablation of an mRNA target by 2-5A antisense chimeras. , 1994, Science.

[2]  L Bibbs,et al.  A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. , 1994, Science.

[3]  D. Levy,et al.  Ras-independent growth factor signaling by transcription factor tyrosine phosphorylation. , 1993, Science.

[4]  M. Bollen,et al.  Inactivation of nuclear inhibitory polypeptides of protein phosphatase-1 (NIPP-1) by protein kinase A. , 1993, The Journal of biological chemistry.

[5]  S. Goodbourn,et al.  Proteolytic degradation of MAD3 (IϰBα) and enhanced processing of the NF-ϰB precursor p105 are obligatory steps in the activation of NF-ϰB , 1993 .

[6]  L. Zon,et al.  Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1 , 1994, Nature.

[7]  William Arbuthnot Sir Lane,et al.  Isolation of the cyclosporin-sensitive T cell transcription factor NFATp. , 1993, Science.

[8]  K. Anderson,et al.  The spätzle gene encodes a component of the extracellular signaling pathway establishing the dorsal-ventral pattern of the Drosophila embryo , 1994, Cell.

[9]  Masatoshi Hagiwara,et al.  Phosphorylated CREB binds specifically to the nuclear protein CBP , 1993, Nature.

[10]  M. Hagiwara,et al.  Transcriptional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB , 1992, Cell.

[11]  C. Marshall,et al.  MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. , 1994, Current opinion in genetics & development.

[12]  P. Cohen,et al.  EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor , 1994, Current Biology.

[13]  A. Rao.  NF-ATp: a transcription factor required for the co-ordinate induction of several cytokine genes. , 1994, Immunology today.

[14]  M. Hagiwara,et al.  Recombinant cyclic AMP response element binding protein (CREB) phosphorylated on Ser-133 is transcriptionally active upon its introduction into fibroblast nuclei. , 1994, The Journal of biological chemistry.

[15]  S. Wasserman,et al.  pelle encodes a protein kinase required to establish dorsoventral polarity in the Drosophila embryo , 1993, Cell.

[16]  M. Karin,et al.  Ha-Ras augments c-Jun activity and stimulates phosphorylation of its activation domain , 1991, Nature.

[17]  B. Wasylyk,et al.  PEA3 is a nuclear target for transcription activation by non‐nuclear oncogenes. , 1989, The EMBO journal.

[18]  R. Treisman.  Ternary complex factors: growth factor regulated transcriptional activators. , 1994, Current opinion in genetics & development.

[19]  M. Wigler,et al.  Complexes between STE5 and components of the pheromone-responsive mitogen-activated protein kinase module. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[20]  I. Verma,et al.  Transcriptional autoregulation of the proto-oncogene fos , 1988, Nature.

[21]  Gerald M. Rubin,et al.  The activities of two Ets-related transcription factors required for drosophila eye development are modulated by the Ras/MAPK pathway , 1994, Cell.

[22]  C. Schindler,et al.  Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. , 1994, Science.

[23]  M. Read,et al.  Lipopolysaccharide induces phosphorylation of MAD3 and activation of c-Rel and related NF-kappa B proteins in human monocytic THP-1 cells. , 1993, The Journal of biological chemistry.

[24]  G. Sprague,,et al.  Yeast peptide pheromones, a-factor and α-factor, activate a common response mechanism in their target cells , 1986, Cell.

[25]  S. Ruben,et al.  Erratum: IKB interacts with the nuclear localization sequences of the subunits of NF-KB: A mechanism for cytoplasmic retention (Genes and Development (1992) 6 (1899-1913)) , 1992 .

[26]  R. Davis,et al.  MAPKs: new JNK expands the group. , 1994, Trends in biochemical sciences.

[27]  J. Darnell,et al.  Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. , 1992, Science.

[28]  Andrew Ziemiecki,et al.  Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins , 1993, Nature.

[29]  P. Herrlich,et al.  UV‐induced activation of AP‐1 involves obligatory extranuclear steps including Raf‐1 kinase. , 1993, The EMBO journal.

[30]  B. Wasylyk,et al.  The collagenase gene promoter contains a TPA and oncogene‐responsive unit encompassing the PEA3 and AP‐1 binding sites. , 1990, The EMBO journal.

[31]  A. Nordheim,et al.  Occupation of the c-fos serum response element in vivo by a multi-protein complex is unaltered by growth factor induction , 1989, Nature.

[32]  C. Molina,et al.  Inducibility and negative autoregulation of CREM: An alternative promoter directs the expression of ICER, an early response repressor , 1993, Cell.

[33]  Hong Sun,et al.  MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo , 1993, Cell.

[34]  E. Elion,et al.  FUS3 phosphorylates multiple components of the mating signal transduction cascade: evidence for STE12 and FAR1. , 1993, Molecular biology of the cell.

[35]  A. Sharrocks,et al.  Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter , 1992, Nature.

[36]  J. Hancock,et al.  Activation of Raf as a result of recruitment to the plasma membrane. , 1994, Science.

[37]  S. Ruben,et al.  I kappa B interacts with the nuclear localization sequences of the subunits of NF-kappa B: a mechanism for cytoplasmic retention. , 1992, Genes & development.

[38]  A. Rao,et al.  The role of NFATp in cyclosporin A-sensitive tumor necrosis factor-alpha gene transcription. , 1994, The Journal of biological chemistry.

[39]  Michael Levine,et al.  Binding affinities and cooperative interactions with bHLH activators delimit threshold responses to the dorsal gradient morphogen , 1993, Cell.

[40]  I. Herskowitz.  MAP kinase pathways in yeast: For mating and more , 1995, Cell.

[41]  N. Gay,et al.  Drosophila Toll and IL-1 receptor , 1991, Nature.

[42]  A. Baldwin,et al.  The I kappa B proteins: multifunctional regulators of Rel/NF-kappa B transcription factors. , 1993, Genes & development.

[43]  M. Montminy,et al.  Characterization of motifs which are critical for activity of the cyclic AMP-responsive transcription factor CREB , 1991, Molecular and cellular biology.

[44]  T. Maniatis,et al.  The high mobility group protein HMG I(Y) is an essential structural component of a virus-inducible enhancer complex. , 1993, Cold Spring Harbor symposia on quantitative biology.

[45]  M. Karin,et al.  The mammalian ultraviolet response is triggered by activation of src tyrosine kinases , 1992, Cell.

[46]  R. Hipskind,et al.  Ras/MAP kinase-dependent and -independent signaling pathways target distinct ternary complex factors. , 1994, Genes & development.

[47]  Tony Hunter,et al.  The regulation of transcription by phosphorylation , 1992, Cell.

[48]  J. Lis,et al.  Protein traffic on the heat shock promoter: Parking, stalling, and trucking along , 1993, Cell.

[49]  M. Karin,et al.  c-Fos transcriptional activity stimulated by H-Ras-activated protein kinase distinct from JNK and ERK , 1994, Nature.

[50]  S. Akira,et al.  Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway , 1994, Cell.

[51]  J. Darnell,et al.  A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. , 1993, Science.

[52]  Masahiko Hibi,et al.  JNK is involved in signal integration during costimulation of T lymphocytes , 1994, Cell.

[53]  M. Gilman,et al.  Distinct protein targets for signals acting at the c-fos serum response element. , 1991, Science.

[54]  R. Kingston,et al.  Hydrophobic coiled-coil domains regulate the subcellular localization of human heat shock factor 2. , 1993, Genes & development.

[55]  Ernst Hafen,et al.  The ETS domain protein Pointed-P2 is a target of MAP kinase in the Sevenless signal transduction pathway , 1994, Nature.

[56]  Michel Morange,et al.  A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins , 1994, Cell.

[57]  G. Ammerer.  Sex, stress and integrity: the importance of MAP kinases in yeast. , 1994, Current opinion in genetics & development.

[58]  P. Baeuerle,et al.  Function and activation of NF-kappa B in the immune system. , 1994, Annual review of immunology.

[59]  L. Zon,et al.  Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun , 1994, Nature.

[60]  P. Shaw,et al.  Inhibition of v-raf-dependent c-fos expression and transformation by a kinase-defective mutant of the mitogen-activated protein kinase Erk2 , 1994, Molecular and cellular biology.

[61]  Tom Maniatis,et al.  The ubiquitinproteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB , 1994, Cell.

[62]  M. C. Ellis,et al.  Drosophila Jun mediates Ras-dependent photoreceptor determination , 1994, Cell.

[63]  J. Hsuan,et al.  Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of hsp27 , 1994, Cell.

[64]  S. McKnight,et al.  An interleukin-4-induced transcription factor: IL-4 Stat. , 1994, Science.

[65]  A. Israël,et al.  Promoter analysis of the gene encoding the I kappa B‐alpha/MAD3 inhibitor of NF‐kappa B: positive regulation by members of the rel/NF‐kappa B family. , 1993, The EMBO journal.

[66]  M. Montminy,et al.  The cAMP-regulated transcription factor CREB interacts with a component of the TFIID complex. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[67]  F H Bach,et al.  NK-kappa B subunit-specific regulation of the I kappa B alpha promoter. , 1994, The Journal of biological chemistry.

[68]  H. K. Sluss,et al.  Signal transduction by tumor necrosis factor mediated by JNK protein kinases , 1994, Molecular and cellular biology.

[69]  A. Goldberg,et al.  The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. , 1994, Cell.

[70]  R. Treisman,et al.  Serum‐regulated transcription by serum response factor (SRF): a novel role for the DNA binding domain. , 1994, The EMBO journal.

[71]  C. Nüsslein-Volhard,et al.  The origin of pattern and polarity in the Drosophila embryo , 1992, Cell.

[72]  T. Curran,et al.  The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun , 1993, Nature.

[73]  G. Nolan,et al.  NF-AT components define a family of transcription factors targeted in T-cell activation , 1994, Nature.

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

[75]  J. Westwood,et al.  Activation of Drosophila heat shock factor: conformational change associated with a monomer-to-trimer transition , 1993, Molecular and cellular biology.

[76]  A. Kraft,et al.  Phorbol esters stimulate the phosphorylation of c-Jun but not v-Jun: regulation by the N-terminal delta domain. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[77]  M. Levine,et al.  Dif, a dorsal-related gene that mediates an immune response in Drosophila , 1993, Cell.

[78]  Xin-Yuan Fu,et al.  Transcription factor p91 interacts with the epidermal growth factor receptor and mediates activation of the c-fos gene promoter , 1993, Cell.

[79]  Jun Ma,et al.  An HMG-like protein that can switch a transcriptional activator to a repressor , 1994, Nature.

[80]  M. Greenberg,et al.  A growth factor-induced kinase phosphorylates the serum response factor at a site that regulates its DNA-binding activity , 1993, Molecular and cellular biology.

[81]  E. Elion,et al.  Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae , 1994, Cell.

[82]  M. Gilman,et al.  Dual modes of control of c-fos mRNA induction by intracellular calcium in T cells , 1994, Molecular and cellular biology.

[83]  J. Woodgett,et al.  The stress-activated protein kinase subfamily of c-Jun kinases , 1994, Nature.

[84]  James R. Woodgett,et al.  Phosphorylation of c-jun mediated by MAP kinases , 1991, Nature.

[85]  H. Gronemeyer.  Transcription activation by nuclear receptors. , 1993, Journal of receptor research.

[86]  N. Jones,et al.  Different binding specificities and transactivation of variant CRE's by CREB complexes. , 1994, Nucleic acids research.

[87]  M. Karin,et al.  Activation of cAMP and mitogen responsive genes relies on a common nuclear factor , 1994, Nature.

[88]  R. Kolesnick,et al.  The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling , 1994, Cell.

[89]  G. Crabtree,et al.  Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A , 1991, Nature.

[90]  M. Greenberg,et al.  Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB , 1994, Cell.

[91]  Ivan Dikic,et al.  PC12 cells overexpressing the insulin receptor undergo insulin-dependent neuronal differentiation , 1994, Current Biology.

[92]  Y. Ben-Neriah,et al.  Rapid proteolysis of IκB-α is necessary for activation of transcription factor NF-κB , 1993, Nature.

[93]  I. Verma,et al.  Enhanced I kappa B alpha degradation is responsible for constitutive NF-kappa B activity in mature murine B-cell lines , 1994, Molecular and cellular biology.

[94]  S. Cohen,et al.  Induction by EGF and interferon-gamma of tyrosine phosphorylated DNA binding proteins in mouse liver nuclei. , 1993, Science.

[95]  C. Rushlow,et al.  Conversion of a silencer into an enhancer: evidence for a co‐repressor in dorsal‐mediated repression in Drosophila. , 1993, The EMBO journal.

[96]  L. Lau,et al.  Activation of the inducible orphan receptor gene nur77 by serum growth factors: dissociation of immediate-early and delayed-early responses , 1993, Molecular and cellular biology.

[97]  K. Matsumoto,et al.  MSG5, a novel protein phosphatase promotes adaptation to pheromone response in S. cerevisiae. , 1994, The EMBO journal.

[98]  D. Brenner,et al.  Oncogenic Ras activates c-Jun via a separate pathway from the activation of extracellular signal-regulated kinases. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[99]  A. Baldwin,et al.  Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation , 1993, Molecular and cellular biology.

[100]  M. Karin,et al.  Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. , 1993, Genes & development.

[101]  C. Marshall,et al.  Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation , 1995, Cell.

[102]  D R Alessi,et al.  The human CL100 gene encodes a Tyr/Thr-protein phosphatase which potently and specifically inactivates MAP kinase and suppresses its activation by oncogenic ras in Xenopus oocyte extracts. , 1993, Oncogene.

[103]  S. Roth,et al.  The global transcriptional regulators, SSN6 and TUP1, play distinct roles in the establishment of a repressive chromatin structure. , 1994, Genes & development.

[104]  O. Silvennoinen,et al.  Signaling by the cytokine receptor superfamily: JAKs and STATs. , 1994, Trends in biochemical sciences.

[105]  I. Tsigelny,et al.  JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. , 1994, Genes & development.

[106]  J R Feramisco,et al.  Expression of a peptide inhibitor of protein phosphatase 1 increases phosphorylation and activity of CREB in NIH 3T3 fibroblasts , 1994, Molecular and cellular biology.

[107]  Sally J. Leevers,et al.  Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane , 1994, Nature.

[108]  M. Levine,et al.  Conversion of a dorsal‐dependent silencer into an enhancer: evidence for dorsal corepressors. , 1993, The EMBO journal.

[109]  M. Montminy,et al.  Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133 , 1989, Cell.

[110]  M. Greenberg,et al.  Effect of protein synthesis inhibitors on growth factor activation of c-fos, c-myc, and actin gene transcription , 1986, Molecular and cellular biology.

[111]  S. Fields,et al.  Coupling of cell identity to signal response in yeast: interaction between the alpha 1 and STE12 proteins. , 1993, Genes & development.

[112]  Michael R. Green,et al.  Nuclear protein CBP is a coactivator for the transcription factor CREB , 1994, Nature.

[113]  A. Nordheim,et al.  Activation of ternary complex factor Elk‐1 by MAP kinases. , 1993, The EMBO journal.

[114]  I. Kerr,et al.  Activation of JAK kinases and STAT proteins by interleukin‐2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. , 1994, The EMBO journal.

[115]  G L Johnson,et al.  Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. , 1994, Science.

[116]  Tony Hunter,et al.  Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity , 1991, Cell.

[117]  L. Mahadevan,et al.  Signalling and superinduction , 1991, Nature.

[118]  B. Viviano,et al.  Ligand‐induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91). , 1994, The EMBO journal.

[119]  Aseem Kumar,et al.  Double-stranded RNA-dependent protein kinase activates transcription factor NF-kappa B by phosphorylating I kappa B. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[120]  M. Greenberg,et al.  CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. , 1991, Science.

[121]  B. Jakobsen,et al.  A short element required for turning off heat shock transcription factor: evidence that phosphorylation enhances deactivation. , 1994, The EMBO journal.

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

[123]  M. Levine,et al.  Regulation of the dorsal morphogen by the Toll and torso signaling pathways: a receptor tyrosine kinase selectively masks transcriptional repression. , 1994, Genes & development.

[124]  E. Lalli,et al.  Signal transduction and gene regulation: the nuclear response to cAMP. , 1994, The Journal of biological chemistry.

[125]  B. Williams,et al.  Interferon-alpha activates binding of nuclear factors to a sequence element in the c-fos proto-oncogene 5'-flanking region. , 1992, Journal of Interferon Research.

[126]  M. Montminy,et al.  Protein-kinase-A-dependent activator in transcription factor CREB reveals new role for CREM repressers , 1993, Nature.

[127]  M. Karin,et al.  JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain , 1994, Cell.

[128]  B. Groner,et al.  Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. , 1995, The EMBO journal.