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Proteolysis of MLL family proteins is essential for taspase1-orchestrated cell cycle progression.

Taspase1 was identified as the threonine endopeptidase that cleaves mixed-lineage leukemia (MLL) for proper Hox gene expression in vitro. To investigate its functions in vivo, we generated Taspase1(-/-) mice. Taspase1 deficiency results in noncleavage (nc) of MLL and MLL2 and homeotic transformations. Remarkably, our in vivo studies uncover an unexpected role of Taspase1 in the cell cycle. Taspase1(-/-) animals are smaller in size. Taspase1(-/-) mouse embryonic fibroblasts (MEFs) exhibit impaired proliferation, and acute deletion of Taspase1 leads to a marked reduction of thymocytes. Taspase1 deficiency incurs down-regulation of Cyclin Es, As, and Bs and up-regulation of p16(Ink4a) . We show that MLL and MLL2 directly target E2Fs for Cyclin expression. The uncleaved precursor MLL displays a reduced histone H3 methyl transferase activity in vitro. Accordingly, chromatin immunoprecipitation assays demonstrate a markedly decreased histone H3 K4 trimethylation at Cyclin E1 and E2 genes in Taspase1(-/-) cells. Furthermore, MLL(nc/nc;2nc/nc) MEFs are also impaired in proliferation. 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 overexpressed in many cancer cell lines. Thus, Taspase1 may serve as a target for cancer therapeutics.

Pubmed ID: 16951254


  • Takeda S
  • Chen DY
  • Westergard TD
  • Fisher JK
  • Rubens JA
  • Sasagawa S
  • Kan JT
  • Korsmeyer SJ
  • Cheng EH
  • Hsieh JJ


Genes & development

Publication Data

September 1, 2006

Associated Grants

  • Agency: NCI NIH HHS, Id: CA R01-119008

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Animals, Newborn
  • Cell Cycle
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Endopeptidases
  • Hydrolysis
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Myeloid-Lymphoid Leukemia Protein