STAT proteins: From normal control of cellular events to tumorigenesis

Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors latent in the cytoplasm that participate in normal cellular events, such as differentiation, proliferation, cell survival, apoptosis, and angiogenesis following cytokine, growth factor, and hormone signaling. STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulates process. Nevertheless, several constitutively activated STATs have been observed in a wide number of human cancer cell lines and primary tumors, including blood malignancies and solid neoplasias. STATs can be divided into two groups according to their specific functions. One is made up of STAT2, STAT4, and STAT6, which are activated by a small number of cytokines and play a distinct role in the development of T‐cells and in IFNγ signaling. The other group includes STAT1, STAT3, and STAT5, activated in different tissues by means of a series of ligands and involved in IFN signaling, development of the mammary gland, response to GH, and embriogenesis. This latter group of STATS plays an important role in controlling cell‐cycle progression and apoptosis and thus contributes to oncogenesis. Although an increased expression of STAT1 has been observed in many human neoplasias, this molecule can be considered a potential tumor suppressor, since it plays an important role in growth arrest and in promoting apoptosis. On the other hand, STAT3 and 5 are considered as oncogenes, since they bring about the activation of cyclin D1, c‐Myc, and bcl‐xl expression, and are involved in promoting cell‐cycle progression, cellular transformation, and in preventing apoptosis. J. Cell. Physiol. 197: 157–168, 2003© 2003 Wiley‐Liss, Inc.

[1]  G. Stark,et al.  Association of STATs with relatives and friends. , 2000, Trends in cell biology.

[2]  B. Williams,et al.  p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons , 1999, The EMBO journal.

[3]  G. Stark,et al.  How Stat1 mediates constitutive gene expression: a complex of unphosphorylated Stat1 and IRF1 supports transcription of the LMP2 gene , 2000, The EMBO journal.

[4]  R. Arceci,et al.  STAT3 activation is required for Asp816 mutant c-Kit induced tumorigenicity , 2001, Oncogene.

[5]  D. Hilton,et al.  SOCS Proteins: Negative Regulators of Cytokine Signaling , 2001, Stem cells.

[6]  J. Grandis,et al.  Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth In vitro. , 1998, The Journal of clinical investigation.

[7]  P. Doherty,et al.  Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells , 1996, Nature.

[8]  J. Baselga.  New therapeutic agents targeting the epidermal growth factor receptor. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  J. Grandis,et al.  STAT signaling in head and neck cancer , 2000, Oncogene.

[10]  A. Levitzki,et al.  Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor , 1996, Nature.

[11]  W. Alexander,et al.  Negative Regulators of Cytokine Signaling , 2001, International journal of hematology.

[12]  B. Nelson,et al.  The IL-2 Receptor Promotes Lymphocyte Proliferation and Induction of the c-myc, bcl-2, and bcl-x Genes Through the trans-Activation Domain of Stat51 , 2000, The Journal of Immunology.

[13]  D. Yee,et al.  STAT6 mediates interleukin-4 growth inhibition in human breast cancer cells. , 2002, Neoplasia.

[14]  W. Hiddemann,et al.  Constitutive activation of STAT3 and STAT5 is induced by leukemic fusion proteins with protein tyrosine kinase activity and is sufficient for transformation of hematopoietic precursor cells. , 2002, Experimental hematology.

[15]  J. Williams,et al.  STAT signalling in cell proliferation and in development. , 2000, Current opinion in genetics & development.

[16]  R. Jove,et al.  Drug resistance in multiple myeloma: approaches to circumvention. , 1999, Seminars in oncology.

[17]  D. Yee,et al.  Interleukin 4 inhibits growth and induces apoptosis in human breast cancer cells. , 1998, Cancer Research.

[18]  J. Baselga.  Current and planned clinical trials with trastuzumab (Herceptin). , 2000, Seminars in oncology.

[19]  G. Stark,et al.  How cells respond to interferons. , 1998, Annual review of biochemistry.

[20]  S. Becker,et al.  Three-dimensional structure of the Stat3β homodimer bound to DNA , 1998, Nature.

[21]  A. Bridges,et al.  Anticancer efficacy of the irreversible EGFr tyrosine kinase inhibitor PD 0169414 against human tumor xenografts , 2000, Cancer Chemotherapy and Pharmacology.

[22]  Hua Yu,et al.  Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells , 2001, Oncogene.

[23]  J. Lammers,et al.  STAT 5 Activation by BCR-Abl Contributes to Transformation of K 562 Leukemia Cells , 1999 .

[24]  Michael P. Brown,et al.  Stat5a and Stat5b Proteins Have Essential and Nonessential, or Redundant, Roles in Cytokine Responses , 1998, Cell.

[25]  S. Akira.  Roles of STAT3 defined by tissue-specific gene targeting , 2000, Oncogene.

[26]  J. Turkson,et al.  Activation of Stat3 in v-Src-transformed Fibroblasts Requires Cooperation of Jak1 Kinase Activity* , 2000, The Journal of Biological Chemistry.

[27]  R. Schreiber,et al.  Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Thomas S. Lin,et al.  STAT signaling in the pathogenesis and treatment of leukemias , 2000, Oncogene.

[29]  R. Hofstra,et al.  MEN2A-RET-induced cellular transformation by activation of STAT3 , 2001, Oncogene.

[30]  O. Bernard,et al.  TEL-JAK2 transgenic mice develop T-cell leukemia. , 2000, Blood.

[31]  K. Shuai.  The STAT family of proteins in cytokine signaling. , 1999, Progress in biophysics and molecular biology.

[32]  L. Ellis,et al.  Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis , 2002, Oncogene.

[33]  C. Sawyers,et al.  Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. , 1996, Oncogene.

[34]  S. Akira,et al.  Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. , 1999, Genes & development.

[35]  C. Schindler,et al.  Interferons as a paradigm for cytokine signal transduction , 1999, Cellular and Molecular Life Sciences CMLS.

[36]  N. Hamasaki,et al.  Constitutive activation of Jak‐2 and Tyk‐2 in a v‐Src‐transformed human gallbladder adenocarcinoma cell line , 1998, Journal of cellular physiology.

[37]  Jiayuh Lin,et al.  Constitutive activation of stat 3 oncogene product in human ovarian carcinoma cells. , 2000, Gynecologic oncology.

[38]  J. Darnell,et al.  The role of STATs in transcriptional control and their impact on cellular function , 2000, Oncogene.

[39]  R. Starzyk.  tRNA base modifications and gene regulation , 1984 .

[40]  L. Bruhn,et al.  PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. , 2001, Genes & development.

[41]  Aseem Kumar,et al.  Defective TNF-α-Induced Apoptosis in STAT1-Null Cells Due to Low Constitutive Levels of Caspases , 1997 .

[42]  B. Nelson,et al.  Stat5 and Sp1 Regulate Transcription of the Cyclin D2 Gene in Response to IL-21 , 2001, The Journal of Immunology.

[43]  R. Jove,et al.  Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

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

[45]  K Imada,et al.  The Jak-STAT pathway. , 2000, Molecular immunology.

[46]  C. Schindler,et al.  A Stat3-interacting protein (StIP1) regulates cytokine signal transduction. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[47]  G. Fuller,et al.  Constitutive activation of Stat3α in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2) , 2002, Oncogene.

[48]  S. Akira,et al.  Keratinocyte‐specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis , 1999, The EMBO journal.

[49]  R. Jove,et al.  Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. , 1997, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[50]  A. Mui,et al.  STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells , 1999, The EMBO journal.

[51]  J. Turkson,et al.  Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. , 2001, The Journal of clinical investigation.

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

[53]  T. Decker,et al.  Transcription factor activity of STAT proteins: structural requirements and regulation by phosphorylation and interacting proteins , 1999, Cellular and Molecular Life Sciences CMLS.

[54]  T. Hirano,et al.  STAT3 orchestrates contradictory signals in cytokine‐induced G1 to S cell‐cycle transition , 1998, The EMBO journal.

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

[56]  J. Ihle,et al.  Phosphorylation and Activation of the DNA Binding Activity of Purified Stat1 by the Janus Protein-tyrosine Kinases and the Epidermal Growth Factor Receptor (*) , 1995, The Journal of Biological Chemistry.

[57]  R. Jove,et al.  STAT5 activation by BCR-Abl contributes to transformation of K562 leukemia cells. , 1999, Blood.

[58]  T. Yeatman,et al.  Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[59]  Roy Garcia,et al.  STATs in oncogenesis , 2000, Oncogene.

[60]  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.

[61]  J. Williams.  Serpentine receptors and STAT activation: more than one way to twin a STAT. , 1999, Trends in biochemical sciences.

[62]  L. Koenderman,et al.  STAT5-Dependent CyclinD1 and Bcl-xL expression in Bcr-Abl-transformed cells. , 2000, Molecular cell biology research communications : MCBRC.

[63]  S. Burakoff,et al.  Cytosolic Tyrosine Dephosphorylation of STAT5 , 2000, The Journal of Biological Chemistry.

[64]  V. Nicoletti,et al.  Role of the JAK/STAT Signal Transduction Pathway in the Regulation of Gene Expression in CNS , 2004, Neurochemical Research.

[65]  R. Snell,et al.  Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[66]  E. Petricoin,et al.  Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. , 1995, Science.

[67]  S. Bhattacharya,et al.  Signaling through the JAK/STAT pathway, recent advances and future challenges. , 2002, Gene.

[68]  K. Shuai,et al.  Modulation of STAT signaling by STAT-interacting proteins , 2000, Oncogene.

[69]  M. Loh,et al.  Stat5 is essential for the myelo- and lymphoproliferative disease induced by TEL/JAK2. , 2000, Molecular cell.

[70]  Itaru Matsumura,et al.  Transcriptional regulation of the cyclin D1 promoter by STAT5: its involvement in cytokine‐dependent growth of hematopoietic cells , 1999, The EMBO journal.

[71]  H. Lodish,et al.  Fetal Anemia and Apoptosis of Red Cell Progenitors in Stat5a−/−5b−/− Mice A Direct Role for Stat5 in Bcl-XL Induction , 1999, Cell.

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

[73]  Mikhail Chernov,et al.  Regulation of c‐myc expression by IFN‐γ through Stat1‐dependent and ‐independent pathways , 2000 .

[74]  Pavel Kovarik,et al.  Serine phosphorylation of STATs , 2000, Oncogene.

[75]  C. Horvath,et al.  STAT proteins and transcriptional responses to extracellular signals. , 2000, Trends in biochemical sciences.

[76]  J. Darnell,et al.  The Linker Domain of Stat1 Is Required for Gamma Interferon-Driven Transcription , 1999, Molecular and Cellular Biology.

[77]  M. Gadina,et al.  Advances in cytokine signaling: the role of Jaks and STATs. , 1999, Transplantation proceedings.

[78]  J. Briscoe,et al.  JAKs and STATs branch out. , 1996, Trends in cell biology.

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

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

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

[82]  N. Danial,et al.  Jak-STAT signaling induced by the v-abl oncogene. , 1995, Science.

[83]  D. Hilton,et al.  Negative regulation of the JAK/STAT pathway , 1999, BioEssays : news and reviews in molecular, cellular and developmental biology.

[84]  P Jay,et al.  Specific inhibition of Stat3 signal transduction by PIAS3. , 1997, Science.

[85]  J. Turkson,et al.  Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated STAT3 signaling , 2000, Oncogene.

[86]  J. Bromberg.  Stat proteins and oncogenesis. , 2002, The Journal of clinical investigation.

[87]  Satoru Shiono,et al.  Control mechanism of JAK/STAT signal transduction pathway , 2003, FEBS letters.

[88]  J. Aster,et al.  Transformation of hematopoietic cell lines to growth‐factor independence and induction of a fatal myelo‐ and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes , 1998, The EMBO journal.

[89]  Mutsuko Ouchi,et al.  Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-gamma target genes. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[90]  C. Schindler,et al.  Series Introduction: JAK-STAT signaling in human disease , 2002 .

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

[92]  H. Abboud,et al.  Association and direct activation of signal transducer and activator of transcription1alpha by platelet-derived growth factor receptor. , 1998, The Journal of clinical investigation.

[93]  D. Levy,et al.  What does Stat3 do? , 2002, The Journal of clinical investigation.

[94]  F. Gouilleux,et al.  IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line , 1999, Oncogene.

[95]  W. Leonard,et al.  Stat5b Is Essential for Natural Killer Cell–mediated Proliferation and Cytolytic Activity , 1998, The Journal of experimental medicine.

[96]  G. Feng,et al.  Shp-2 Tyrosine Phosphatase Functions as a Negative Regulator of the Interferon-Stimulated Jak/STAT Pathway , 1999, Molecular and Cellular Biology.

[97]  J. Darnell,et al.  Stat3 as an Oncogene , 1999, Cell.

[98]  J. Darnell,et al.  Stat3 Activation Is Required for Cellular Transformation by v-src , 1998, Molecular and Cellular Biology.

[99]  J. Turkson,et al.  Stat3 Activation by Src Induces Specific Gene Regulation and Is Required for Cell Transformation , 1998, Molecular and Cellular Biology.

[100]  M. Tremblay,et al.  The T Cell Protein Tyrosine Phosphatase Is a Negative Regulator of Janus Family Kinases 1 and 3 , 2002, Current Biology.

[101]  S. Akira,et al.  STAT family of transcription factors in cytokine-mediated biological responses. , 2000, Cytokine & growth factor reviews.

[102]  F. Prósper,et al.  Erythropoietin Can Induce the Expression of Bcl-xLthrough Stat5 in Erythropoietin-dependent Progenitor Cell Lines* , 1999, The Journal of Biological Chemistry.

[103]  J. Turkson,et al.  Phosphotyrosyl Peptides Block Stat3-mediated DNA Binding Activity, Gene Regulation, and Cell Transformation* , 2001, The Journal of Biological Chemistry.

[104]  J. Darnell,et al.  The Significance of Tetramerization in Promoter Recruitment by Stat5 , 1999, Molecular and Cellular Biology.

[105]  B. Elliott,et al.  Co-operative Effect of c-Src Tyrosine Kinase and Stat3 in Activation of Hepatocyte Growth Factor Expression in Mammary Carcinoma Cells* , 2001, The Journal of Biological Chemistry.

[106]  M. Crompton,et al.  Expression of v-src in mammary epithelial cells induces transcription via STAT3. , 1998, The Biochemical journal.

[107]  J. ten Hoeve,et al.  Identification of a Nuclear Stat1 Protein Tyrosine Phosphatase , 2002, Molecular and Cellular Biology.

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

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

[110]  S. Akira,et al.  Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[111]  R. Schreiber,et al.  Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice , 1998 .

[112]  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.

[113]  J. Marine,et al.  A small amphipathic α‐helical region is required for transcriptional activities and proteasome‐dependent turnover of the tyrosine‐phosphorylated Stat5 , 2000, The EMBO journal.

[114]  Xin-Yuan Fu,et al.  Cell Growth Arrest and Induction of Cyclin-Dependent Kinase Inhibitor p21WAF1/CIP1 Mediated by STAT1 , 1996, Science.

[115]  J. Grandis,et al.  Requirement of Stat 3 but not Stat 1 Activation for Epidermal Growth Factor Receptor – mediated Cell Growth In Vitro , 1998 .

[116]  P. Coffer,et al.  The role of STATs in myeloid differentiation and leukemia , 2000, Oncogene.

[117]  A nuclear protein tyrosine phosphatase TC-PTP is a potential negative regulator of the PRL-mediated signaling pathway: dephosphorylation and deactivation of signal transducer and activator of transcription 5a and 5b by TC-PTP in nucleus. , 2002, Molecular endocrinology.

[118]  D. Levy,et al.  What does Stat 3 do ? , 2002 .

[119]  R. Jove,et al.  STAT proteins as novel targets for cancer therapy. Signal transducer an activator of transcription. , 1999, Current opinion in oncology.

[120]  L. Hennighausen,et al.  Stat5a is mandatory for adult mammary gland development and lactogenesis. , 1997, Genes & development.

[121]  G. Stark,et al.  Cooperative binding of Stat1-2 heterodimers and ISGF3 to tandem DNA elements. , 1998, Biochimie.