Abstract
Expression of the immediate early protein tristetraprolin (TTP) is induced by numerous stimuli, including tumor necrosis factor-alpha (TNFα). Evidence indicates that TTP limits production of TNFα and other cytokines by directly binding and destabilizing their mRNAs. This effect seems to require only the conserved TTP zinc finger region, and is characteristic of the related proteins TIS11b and TIS11d. TTP, TIS11b, and TIS11d each also induce apoptosis through the mitochondrial pathway analogously to certain oncogenes, suggesting that they influence growth or survival signals. Among TTP/TIS11 proteins, TTP alone also promotes apoptosis synergistically with TNFα. Here we show that other regions of TTP along with the zinc fingers are required for TTP to induce apoptosis. We also demonstrate that TTP acts through an additional pathway to sensitize cells to the pro-apoptotic stimulus of TNFα. This modulation of TNFα responses specifically requires the TTP N-terminal region, which is not conserved in TIS11b or TIS11d. We conclude that the physiological functions of TTP depend upon multiple regions of the TTP protein, that TTP has diverged functionally from TIS11b and TIS11d, and that modulation of TNFα responses may be a unique and important aspect of TTP function.
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
Bai C, Tolias PP . 1996 Mol. Cell. Biol. 16: 6661–6667
Baker SJ, Reddy EP . 1996 Oncogene 12: 1–9
Barabino SM, Hubner W, Jenny A, Minvielle-Sebastia L, Keller W . 1997 Genes Dev. 11: 1703–1716
Batchelder C, Dunn MA, Choy B, Suh Y, Cassie C, Shim EY, Shin TH, Mello C, Seydoux G, Blackwell TK . 1999 Genes Dev. 13: 202–212
Carballo E, Cao H, Lai WS, Kennington EA, Campbell D, Blackshear PJ . 2001 J. Biol. Chem. 276: 42580–42587
Carballo E, Gilkeson GS, Blackshear PJ . 1997 J. Clin. Invest. 100: 986–995
Carballo E, Lai WS, Blackshear PJ . 1998 Science 281: 1001–1005
Carballo E, Lai WS, Blackshear PJ . 2000 Blood 95: 1891–1899
Chen CY, Gherzi R, Ong SE, Chan EL, Raijmakers R, Pruijn GJ, Stoecklin G, Moroni C, Mann M, Karin M . 2001 Cell 107: 451–464
Chen CY, Shyu AB . 1995 Trends Biochem. Sci. 20: 465–470
Chen MJ, Holskin B, Strickler J, Gorniak J, Clark MA, Johnson PJ, Mitcho M, Shalloway D . 1987 Nature 330: 581–583
DuBois RN, Bishop PR, Graves-Deal R, Coffey RJ . 1995 Cell. Growth Differ. 6: 523–529
DuBois RN, McLane MW, Ryder K, Lau LF, Nathans D . 1990 J. Biol. Chem. 265: 19185–19191
Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin JH, Patriotis C, Jenkins NA, Copeland NG, Kollias G, Tsichlis PN . 2000 Cell 103: 1071–1083
Ehrenfried JA, Townsend Jr CM, Thompson JC, Evers BM . 1995 Ann. Surg. 222: 51–56
Green DR . 2000 Cell 102: 1–4
Guedes S, Priess J . 1997 Development 124: 731–739
Haas CA, Donath C, Kreutzberg GW . 1993 Neuroscience 53: 91–99
Harkin DP, Bean JM, Miklos D, Song YH, Truong VB, Englert C, Christians FC, Ellisen LW, Maheswaran S, Oliner JD, Haber DA . 1999 Cell 97: 575–586
Heximer SP, Forsdyke DR . 1993 DNA Cell. Biol. 12: 73–88
Janicke RU, Lee FH, Porter AG . 1994 Mol. Cell. Biol. 14: 5661–5670
Johnson BA, Geha M, Blackwell TK . 2000 Oncogene 19: 1657–1664
Johnson BA, Stehn JR, Yaffe MB, Blackwell TK . 2002 J. Biol. Chem. Published on line
Klefstrom J, Arighi E, Littlewood T, Jaattela M, Saksela E, Evan GI, Alitalo K . 1997 EMBO J. 16: 7382–7392
Kontoyiannis D, Kotlyarov A, Carballo E, Alexopoulou L, Blackshear PJ, Gaestel M, Davis R, Flavell R, Kollias G . 2001 EMBO J. 20: 3760–3770
Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G . 1999 Immunity 10: 387–398
Kotlyarov A, Neininger A, Schubert C, Eckert R, Birchmeier C, Volk HD, Gaestel M . 1999 Nat. Cell. Biol. 1: 94–97
Lai WS, Blackshear PJ . 2001 J. Biol. Chem. 276: 23144–23154
Lai WS, Carballo E, Strum JR, Kennington EA, Phillips RS, Blackshear PJ . 1999 Mol. Cell. Biol. 19: 4311–4323
Lai WS, Carballo E, Thorn JM, Kennington EA, Blackshear PJ . 2000 J. Biol. Chem. 275: 17827–17837
Lai WS, Kennington EA, Blackshear PJ . 2002 J. Biol. Chem. 277: 9606–9613
Lai WS, Stumpo DJ, Blackshear PJ . 1990 J. Biol. Chem. 265: 16556–16563
Landesberg LJ, Ramalingam R, Lee K, Rosengart TK, Crystal RG . 2001 Am. J. Physiol. Lung Cell. Mol. Physiol. 281: L1138–L1149
Mahtani KR, Brook M, Dean JL, Sully G, Saklatvala J, Clark AR . 2001 Mol. Cell. Biol. 21: 6461–6469
Mesner PW, Epting CL, Hegarty JL, Green SH . 1995 J. Neurosci. 15: 7357–7366
Ming XF, Stoecklin G, Lu M, Looser R, Moroni C . 2001 Mol. Cell. Biol. 21: 5778–5789
Mittelstadt PR, DeFranco AL . 1993 J. Immunol. 150: 4822–4832
Nakajima K, Wall R . 1991 Mol. Cell. Biol. 11: 1409–1418
Pennington KN, Taylor JA, Bren GD, Paya CV . 2001 Mol. Cell. Biol. 21: 1930–1941
Phillips AC, Ernst MK, Bates S, Rice NR, Vousden KH . 1999 Mol. Cell. 4: 771–781
Phillips R, Ramos S, Blackshear PJ . 2002 J. Biol. Chem. 277: 11606–11613
Raghavan A, Robison RL, McNabb J, Miller CR, Williams DA, Bohjanen PR . 2001 J. Biol. Chem. 276: 47958–47965
Ray CA, Black RA, Kronheim SR, Greenstreet TA, Sleath PR, Salvesen GS, Pickup DJ . 1992 Cell 69: 597–604
Reese KJ, Dunn MA, Waddle JA, Seydoux G . 2000 Mol. Cell. 6: 445–455
Rutault K, Hazzalin CA, Mahadevan LC . 2001 J. Biol. Chem. 276: 6666–6674
Schubert CM, Lin R, de Vries CJ, Plasterk RH, Priess JR . 2000 Mol. Cell. 5: 671–682
Tabara H, Hill RJ, Mello CC, Priess JR, Kohara Y . 1999 Development 126: 1–11
Taylor GA, Carballo E, Lee DM, Lai WS, Thompson MJ, Patel DD, Schenkman DI, Gilkeson GS, Broxmeyer HE, Haynes BF, Blackshear PJ . 1996a Immunity 4: 445–454
Taylor GA, Thompson MJ, Lai WS, Blackshear PJ . 1995 J. Biol. Chem. 270: 13341–13347
Taylor GA, Thompson MJ, Lai WS, Blackshear PJ . 1996b Mol. Endocrinol. 10: 140–146
Tenenhaus C, Subramaniam K, Dunn MA, Seydoux G . 2001 Genes Dev. 15: 1031–1040
Turner R, Tjian R . 1989 Science 243: 1689–1694
Varnum BC, Lim RW, Sukhatme VP, Herschman HR . 1989 Oncogene 4: 119–120
Varnum BC, Ma QF, Chi TH, Fletcher B, Herschman HR . 1991 Mol. Cell. Biol. 11: 1754–1758
Vasudevan S, Peltz SW . 2001 Mol. Cell. 7: 1191–1200
Winzen R, Kracht M, Ritter B, Wilhelm A, Chen CY, Shyu AB, Muller M, Gaestel M, Resch K, Holtmann H . 1999 EMBO J. 18: 4969–4980
Zhu W, Brauchle MA, Di Padova F, Gram H, New L, Ono K, Downey JS, Han J . 2001 Am. J. Physiol. Lung Cell. Mol. Physiol. 281: L499–L508
Zuo P, Maniatis T . 1996 Genes Dev. 10: 1356–1368
Acknowledgements
For helpful discussions and critical reading of the manuscript we thank Karl Munger, Grace Gill, Azad Bonni, Valerie Zacny, Michael Yaffe, and Blackwell lab members. Supported by a grant from the NIH to TK Blackwell. (1 R01 CA84418), and an Arthritis Foundation postdoctoral fellowship to BA Johnson.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Johnson, B., Blackwell, T. Multiple tristetraprolin sequence domains required to induce apoptosis and modulate responses to TNFα through distinct pathways. Oncogene 21, 4237–4246 (2002). https://doi.org/10.1038/sj.onc.1205526
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205526
Keywords
This article is cited by
-
Targeting AU-rich element-mediated mRNA decay with a truncated active form of the zinc-finger protein TIS11b/BRF1 impairs major hallmarks of mammary tumorigenesis
Oncogene (2019)
-
ZFP36L1 and ZFP36L2 inhibit cell proliferation in a cyclin D-dependent and p53-independent manner
Scientific Reports (2018)
-
ZFP36 stabilizes RIP1 via degradation of XIAP and cIAP2 thereby promoting ripoptosome assembly
BMC Cancer (2015)
-
Tristetraprolin expression and microRNA-mediated regulation during simian immunodeficiency virus infection of the central nervous system
Molecular Brain (2013)
-
Regulation and localization of endogenous human tristetraprolin
Arthritis Res Ther (2003)