Multiple tristetraprolin sequence domains required to induce apoptosis and modulate responses to TNFalpha through distinct pathways.
Expression of the immediate early protein tristetraprolin (TTP) is induced by numerous stimuli, including tumor necrosis factor-alpha (TNFalpha). Evidence indicates that TTP limits production of TNFalpha 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 TNFalpha. 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 TNFalpha. This modulation of TNFalpha 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 TNFalpha responses may be a unique and important aspect of TTP function.
Johnson
Barbra A
BA
Center for Blood Research and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts, MA 02115, USA.
Blackwell
T Keith
TK
D016475:3T3 Cells / Q000166:cytology; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004268:DNA-Binding Proteins; D004357:Drug Synergism; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D008954:Models, Biological; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000737:chemistry / Q000502:physiology; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014162:Transfection; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D016335:Zinc Fingers / Q000502:physiology
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497553:Zfp36 protein, mouse