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PMID: 16951254 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Genes & development ·Vol. 20 ·No. 17 ·2006-09-01 ·Pages 2397-409

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

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 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.

MeSH Terms
Amino Acid Sequence Animals Animals, Newborn Cell Cycle/genetics,physiology Cell Line Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic/genetics,metabolism Endopeptidases/biosynthesis,deficiency,genetics,physiology Hydrolysis Mice Mice, Knockout Molecular Sequence Data Myeloid-Lymphoid Leukemia Protein/genetics,metabolism
Chemicals
Myeloid-Lymphoid Leukemia Protein Endopeptidases taspase1, human taspase1, mouse
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Takeda Shugaku
Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Chen David Y
Westergard Todd D
Fisher Jill K
Rubens Jeffrey A
Sasagawa Satoru
Kan Jason T
Korsmeyer Stanley J
Cheng Emily H-Y
Hsieh James J-D
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1449406
Published
2006-09-01
Pages
2397-409
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC1560414
Subset
IM
Grants
NCI NIH HHS · CA R01-119008 · United States
External Links
PubMed source DOI: 10.1101/gad.1449406 PMC Full Text View journal details
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