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J. Biol. Chem., Vol. 283, Issue 2, 684-692, January 11, 2008

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Ubiquitination and Degradation of Tal1/SCL Are Induced by Notch Signaling and Depend on Skp2 and CHIP^*

From the Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104

Notch signaling controls diverse eukaryotic differentiation processes in multiple cell types, thus demanding versatile tools with which Notch triggers downstream events. Ubiquitin-mediated proteolysis has previously been shown to be one such tool with which Notch regulates the turnover of the basic helix-loophelix transcription factor, E47. Here, we show that Notch signaling also accelerated the degradation of Tal1/SCL (T cell acute leukemia 1/stem cell leukemia) protein, a basic helix-loop-helix protein involved in the development of hematopoietic, vascular, and neuronal tissues. Notch-induced Tal1/SCL degradation was mediated by ubiquitination and proteasomes. The sequence responsible for Tal1 degradation was localized to a region in the C terminus of Tal1, which is evolutionarily conserved, thus suggesting a functional significance. Analogous to the situation for E47, Notch-induced Tal1/SCL degradation not only required Skp2, a substrate-binding subunit of SCF ubiquitin ligase complexes, but also relied on CHIP, a chaperone-binding protein with a ubiquitin ligase activity. In contrast to the fact that the N-terminal tetratricopeptide region (TPR) domain of CHIP is necessary and sufficient for E47 ubiquitination and degradation, CHIP promoted Tal1 degradation with both chaperone binding and ubiquitin ligase activities, which are mediated by its TPR domain and U box, respectively. Although the TPR domain was not involved in Tal1/SCL binding, it was required for enhancing its degradation. Likewise, the ubiquitin ligase activity of CHIP was dispensable for Tal1/SCL binding but essential for degradation. These findings provide both novel mechanistic insights into the operation of cullin-based ubiquitin ligase complexes and potential means by which Notch and Tal1/SCL regulate eukaryotic development.

Received for publication, June 18, 2007 , and in revised form, October 1, 2007.

^* This work was supported by National Institutes of Health Grants AI056129 and CA77553 (to X.-H. S.). 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.

¹ Holds the Eli Lilly Distinguished Chair for Biomedical Research. To whom correspondence should be addressed: Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104. Tel.: 405-271-7103; Fax: 405-271-7128; E-mail: sunx{at}omrf.ouhsc.edu.

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