Abstract
Stat proteins are latent transcription factors activated by tyrosine phosphorylation downstream of cytokine and growth factor receptors and have been implicated in a variety of cell growth regulatory pathways. Constitutive phosphorylation has also been observed in various transformed cell line and in primary malignant tissue, suggesting that Stat protein activation may contribute to the transformed phenotype. One method to distinguish between a causative role in malignancy as opposed to bystander phosphorylation from the increased tyrosine phosphorylation that accompanies transformation is to investigate cell growth and malignancy in the absence of particular Stat proteins using targeted gene disruptions in transgenic mice. Such studies show that Stat1 primarily mediates growth inhibitory signals and contributes to the host rejection of tumors, and that its activation in transformed cells is not necessary for malignancy. Activation of Stat5 can be both necessary and sufficient for malignant transformation, and single Stat5-target genes have been identified that are critical for heightened proliferation. Nonetheless, some malignancies that are characterized by constitutively phosphorylated Stat5 are not altered by the loss of Stat5 protein. Its role in these cases may be redundant with other transforming events that are in themselves sufficient to cause disease, rendering tyrosine phosphorylation of Stat5 unnecessary in these transformed cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bromberg JF, Fan Z, Brown C, Mendelsohn J and Darnell Jr JE . 1998 Cell Growth Differ 9: 505–512
Bromberg JF, Horvath CM, Wen Z, Schreiber RD and Darnell JE . 1996 Proc Natl Acad Sci USA 93: 7673–7678
Buchmeier NA and Schreiber RD . 1985 Proc Natl Acad Sci USA 82: 7404–7408
Carlesso N, Frank DA and Griffin JD . 1996 J Exp Med 183: 811–820
Catlett-Falcone R, Dalton WS and Jove R . 1999 Curr Opin Oncol 11: 490–496
Chai SK, Nichols GL and Rothman P . 1997 J Immunol 159: 4720–4728
Coffin JD, Florkiewicz RZ, Neumann J, Mort-Hopkins T, Dorn II GW, Lightfoot P, German R, Howles PN, Kier A, O'Toole BA, Sasse J, Gonzalez AM, Baird A and Doetschman T . 1995 Mol Biol Cell 6: 1861–1873
Copeland NG, Gilbert DJ, Schindler C, Zhong Z, Wen Z, Darnell Jr JE, Mui AL, Miyajima A, Quelle FW, Ihle JN and Jenkins NA . 1995 Genomics 29: 225–228
Danial NN, Losman JA, Lu T, Yip N, Krishnan K, Krolewski J, Goff SP, Wang JY and Rothman PB . 1998 Mol Cell Biol 18: 6795–6804
Danial NN, Pernis A and Rothman PB . 1995 Science 269: 1875–1877
Darnell JE . 1997 Science 277: 1630–1635
Durbin JE, Hackenmiller R, Simon MC and Levy DE . 1996 Cell 84: 443–450
Fan XD, Goldberg M and Bloom BR . 1988 Proc Natl Acad Sci USA 85: 5122–5125
Fan XD, Stark GR and Bloom BR . 1989 Mol Cell Biol 9: 1922–1928
Friedman RL, Manly SP, McMahon M, Kerr IM and Stark GR . 1984 Cell 38: 745–755
Ho JM, Beattie BK, Squire JA, Frank DA and Barber DL . 1999 Blood 93: 4354–4364
Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, Vilcek J, Zinkernagel RM and Aguet M . 1993 Science 259: 1742–1745
Hwang SY, Hertzog PJ, Holland LA, Sumarsono SH, Tymms MJ, Hamilton JA, Whitty G, Bertoncello I and Kola I . 1995 Proc Natl Acad Sci USA 92: 11284–11288
Ilaria Jr RL and Van Etten RA . 1996 J Biol Chem 271: 31704–31710
Imada K, Bloom ET, Nakajima H, Horvath-Arcidiacono JA, Udy GB, Davey HW and Leonard WJ . 1998 J Exp Med 188: 2067–2074
Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ and Schreiber RD . 1998 Proc Natl Acad Sci USA 95: 7556–7561
Kumar A, Commane M, Flickinger TW, Horvath CM and Stark GR . 1997 Science 278: 1630–1632
Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffe M, Berthou C, Lessard M, Berger R, Ghysdael J and Bernard OA . 1997 Science 278: 1309–1312
Larner AC, Jonak G, Cheng YS, Korant BD, Knight E and Darnell JE . 1984 Proc Natl Acad Sci USA 81: 6733–6737
Lee CK, Gimeno R and Levy DE . 1999 J Exp Med 190: 1451–1463
Lee CK, Smith E, Gimeno R, Gertner R and Levy DE . 2000 J Immunol 164: 1286–1292
Leveen P, Pekny M, Gebre MS, Swolin B, Larsson E and Betsholtz C . 1994 Genes Dev 8: 1875–1887
Levy DE and Darnell JE . 1990 New Biologist 2: 923–928
Liu X, Robinson GW, Wagner KU, Garrett L, Wynshaw-Boris A and Hennighausen L . 1997 Genes Dev 11: 179–186
Meraz MA, White MJ, Sheehan KCF, Bach EA, Rodig SJ, Dighe AS, Kaplan DH, Riely JK, Greenlund AC, Campbell D, Carver-Moore K, DuBois RN, Clark R, Aguet M and Schreiber RD . 1996 Cell 84: 431–442
Moriggl R, Topham DJ, Teglund S, Sexl V, McKay C, Wang D, Hoffmeyer A, van Deursen J, Sangster MY, Bunting KD, Grosveld GC and Ihle JN . 1999 Immunity 10: 249–259
Müller M, Laxton C, Briscoe J, Schindler C, Improta T, Darnell JE, Stark GR and Kerr IM . 1993 EMBO J 12: 4221–4228
Müller U, Steinhoff U, Reis LFL, Hemmi S, Pavlovic J, Zinkernagel RM and Aguet M . 1994 Science 264: 1918–1921
Nakajima H, Liu XW, Wynshaw-Boris A, Rosenthal LA, Imada K, Finbloom DS, Hennighausen L and Leonard WJ . 1997 Immunity 7: 691–701
Okuda K, Golub TR, Gilliland DG and Griffin JD . 1996 Oncogene 13: 1147–1152
Onishi M, Nosaka T, Misawa K, Mui AL, Gorman D, McMahon M, Miyajima A and Kitamura T . 1998 Mol Cell Biol 18: 3871–3879
Ormandy CJ, Camus A, Barra J, Damotte D, Lucas B, Buteau H, Edery M, Brousse N, Babinet C, Binart N and Kelly PA . 1997 Genes Dev 11: 167–178
Revel M and Chebath J . 1986 Trends Biochem Sci 11: 166–170
Ross TS and Gilliland DG . 1999 J Biol Chem 274: 22328–22336
Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC and Horak I . 1993 Cell 75: 253–261
Sahni M, Ambrosetti DC, Mansukhani A, Gertner R, Levy DE and Basilico C . 1999 Genes Dev 13: 1361–1366
Schindler C, Fu XY, Improta T, Aebersold RH and Darnell JE . 1992 Proc Natl Acad Sci USA 89: 7836–7839
Schwaller J, Frantsve J, Aster J, Williams IR, Tomasson MH, Ross TS, Peeters P, Van Rompaey L, Van Etten RA, Ilaria Jr R, Marynen P and Gilliland DG . 1998 EMBO J 17: 5321–5333
Shuai K, Halpern J, ten Hoeve J, Rao X and Sawyers CL . 1996 Oncogene 13: 247–254
Shuai K, Schindler C, Prezioso VR and Darnell JE . 1992 Science 258: 1808–1812
Sibilia M and Wagner EF . 1995 Science 269: 234–238
Socolovsky M, Fallon AE, Wang S, Brugnara C and Lodish HF . 1999 Cell 98: 181–191
Sternberg DW, Tomasson MH, Carroll M, Kazlauskas A and Gilliland DG . 1999 Blood 94, Suppl 1: 389a
Su WC, Kitagawa M, Xue N, Xie B, Garofalo S, Cho J, Deng C, Horton WA and Fu XY . 1997 Nature 386: 288–292
Suzuki H, Kundig TM, Furlonger C, Wakeham A, Timms E, Matsuyama T, Schmits R, Simard JJ, Ohashi PS, Griesser H et al. 1995 Science 268: 1472–1476
Swihart K, Fruth U, Messmer N, Hug K, Behin R, Huang S, Del Guidice G, Aguet M and Louis JA . 1995 J Exp Med 181: 961–971
Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G and Ihle JN . 1998 Cell 93: 841–850
Threadgill DW, Dlugosz AA, Hansen LA, Tennebaum T, Lichti U, Yee D, LaMantia C, Mourton T, Herrup K, Harris RC et al. 1995 Science 269: 230–234
Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ and Davey HW . 1997 Proc Natl Acad Sci USA 94: 7239–7244
Wakao H, Gouilleux F and Groner B . 1994 EMBO J 13: 2182–2191
Wang Z-E, Reiner SL, Zheng S, Dalton DK and Locksley RM . 1994 J Exp Med 179: 1367–1371
Waxman DJ, Ram PA, Pampori NA and Shapiro BH . 1995 Mol Pharmacol 48: 790–797
Acknowledgements
We thank our many colleagues for helpful discussions and unpublished data, in particular the laboratories of James N Ihle and Claudio Basilico.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Levy, D., Gilliland, D. Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice. Oncogene 19, 2505–2510 (2000). https://doi.org/10.1038/sj.onc.1203480
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1203480
Keywords
This article is cited by
-
SIRT1 ISGylation accelerates tumor progression by unleashing SIRT1 from the inactive state to promote its deacetylase activity
Experimental & Molecular Medicine (2024)
-
Expression of the serotonin receptor 2B in uveal melanoma and effects of an antagonist on cell lines
Clinical & Experimental Metastasis (2018)
-
Antitumour actions of interferons: implications for cancer therapy
Nature Reviews Cancer (2016)
-
A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer
British Journal of Cancer (2015)
-
STAT transcription factors in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention
Leukemia (2014)