Research Abstract:
Our laboratory focuses on understanding how Taspase1 and MLL regulate critical biological pathways with a special emphasis on cancer biology. Specifically, we’d like to utilize combined biochemical and genetic approaches to investigate how the evolutionarily conserved protease, Taspase1, and its substrates such as MLL coordinate essential cellular and developmental processes.
Recurrent human chromosome band 11q23 translocations disrupting MLL gene lead to altered HOX gene expression and human leukemia. We showed that MLL undergoes routine proteolysis generating N-terminal 320kDa and C-terminal 180kDa fragments. We subsequently purified the responsible protease and named it, Taspase1. The discovery of Taspase1 founded a novel class of protesases. In addition to MLL proteins, we also identified precursor TFIIA family proteins as well as the Drosophila HCF protein as bona fide Taspase1 substrates.
MLL is a 500kD nuclear coactivator which plays critical roles in embryonic development, hematopoiesis, stem cells, and cell cycle. We plan to extend our knowledge on MLL beyond Hox gene regulation and study the deregulations of respective signalings caused by leukemogenic MLL-Fusions. The ultimate goal is to provide a detailed blueprint of the MLL regulatory network for a molecular reconstruction of the MLL leukemia.
To investigate Taspase1’s functions in vivo, we generated Taspase1 knockout mice. Our in vivo studies uncover an essential role of Taspase1 in cell cycle regulation. Taspase1-/- MEFs exhibit impaired proliferation. The un-cleaved precursor MLL displays a reduced histone H3 methyl transferase activity in vitro and in vivo. Our data are consistent with a model in which precursor MLLs, activated by Taspase1, target to Cyclins through E2Fs to methylate histone H3 at K4, leading to activation. Lastly, Taspase1-/- cells are resistant to oncogenic transformation and Taspase1 is over-expressed in many cancer cell lines. Thus, Taspase1 may serve as a target for future cancer therapeutics. Accordingly, we are in the process of developing Taspase1 inhibitors for potential cancer therapeutics.
Selected Publications:
Liu H, Cheng E H-Y, and Hsieh JJ-D. Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: A critical regulatory circuit lost in leukemogenic MLL-fusions. Genes and Development 2007 21:2371-2384.
Takeda S, Chen DY, Westergard TD, Fisher JK, Rubens JA, Sasagawa S, Kan JT, Korsmeyer SJ, Cheng EHY, Hsieh JJD. Proteolysis of MLL family proteins is essential for Taspase1-orchestrated cell cycle progression. Genes and Development 2006 20:2397-2409.
Hsieh JJD, Cheng EH, Korsmeyer SJ. Taspase1: A threonine aspartase required for MLL cleavage and proper HOX gene expression. Cell 2003 115:293-303.
Hsieh JJD, Ernst P, Erdjment-Bromage H, Tempst P, Korsmeyer SJ. Proteolytic cleavage of MLL generates a complex of N-terminal and C-terminal fragments that confers protein stability and subnuclear localization. Mol Cell Biol 2003 23:186-194.
Hsieh JJD, Hayward SD. Masking of the CBF1/RBPJk transciptional repression domain by Epstein-Barr virus EBNA2. Science 1995 268:560-563.
Last Updated: 08/07/2008 |