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J. Biol. Chem., Vol. 282, Issue 30, 21962-21972, July 27, 2007

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Survival Factor Withdrawal-induced Apoptosis of TF-1 Cells Involves a TRB2-Mcl-1 Axis-dependent Pathway^*

Kou-Ray Lin, Shern-Fwu Lee^¶, Chien-Min Hung, Chung-Leung Li^||, Hsin-Fang Yang-Yen^**, and Jeffrey J. Y. Yen¹

From the Graduate Institute of Life Science, National Defense Medical Center, Taipei 115, the Institute of Biomedical Sciences, Academia Sinica, Taipei 115, ^¶Taiwan Genome Sciences, Inc., Taipei 115, the ^||Stem Cell Program, Institute of Cellular and Organismic Biology/Genomic Research Center, Academia Sinica, Taipei 115, and the ^**Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan

Tribbles, an atypical protein kinase superfamily member, coordinates cell proliferation, migration, and morphogenesis during the development of Drosophila and Xenopus embryos. Although Tribbles are highly conserved throughout evolution, the physiological functions of mammalian Tribbles family remain largely unclear. Here we report that human TRB2 is a pro-apoptotic molecule that induces apoptosis of cells mainly of the hematopoietic origin. TRB2 mRNA is selectively induced by removal of granulocyte macrophage colony-stimulating factor (GM-CSF) or interleukin-2 from human erythroleukemia-derived TF-1 cell line or activated primary CD4⁺ T cells, respectively. It is, however, not induced by many other treatments that trigger apoptosis of these two cell types. Overexpression of TRB2 activates many apoptotic events observed in GM-CSF-deprived TF-1 cells, including loss of mitochondrial membrane potential, Mcl-1 cleavage/degradation, and activation of Bax and a number of caspases. Specific knockdown of TRB2 significantly suppresses GM-CSF deprivation-induced apoptosis and all apoptotic events mentioned above. Finally, we demonstrate that TRB2-induced cleavage and degradation of Mcl-1 are mediated via a caspase-dependent but proteasome-independent mechanism, and overexpression of Mcl-1 or its upstream activator Akt can markedly overcome the apoptogenic effect of TRB2. Altogether, these results suggest that the TRB2-Mcl-1 axis plays an important role in survival factor withdrawal-induced apoptosis of TF-1 cells.

Received for publication, February 26, 2007 , and in revised form, May 30, 2007.

^* This work was supported in part by the Genomics and Proteomics Program from Academia Sinica, Taiwan, Grant AS92IBMS3 and by National Science Council of Taiwan Grants NSC-93-2320-B-001-030, NSC94-2320-B-001-013, and NSC-95-2320-B-001-002 (to J. J. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Institute of Biomedical Sciences, Academia Sinica No. 128, Section 2, Yen-Jiou-Yuan Rd., Taipei 11529, Taiwan. Tel.: 886-2-2652-3077; Fax: 886-2-2782-9142; E-mail: bmjyen{at}ibms.sinica.edu.tw.

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