Proteolysis of MLL family proteins is essential for Taspase1-orchestrated cell cycle progression (original) (raw)

  1. Shugaku Takeda1,7,
  2. David Y. Chen1,7,
  3. Todd D. Westergard1,7,
  4. Jill K. Fisher5,7,
  5. Jeffrey A. Rubens5,
  6. Satoru Sasagawa1,
  7. Jason T. Kan1,
  8. Stanley J. Korsmeyer5,6,
  9. Emily H.-Y. Cheng1,2,3, and
  10. James J.-D. Hsieh1,2,4,2
  11. 1Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
  12. 2Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
  13. 3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
  14. 4Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
  15. 5Howard Hughes Medical Institute, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
  16. ↵7 These authors contributed equally to this work.

Abstract

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 p16Ink4a . 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, MLLnc/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.

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