The ALL-1 gene located at human chromosome 11q23 is frequently rearranged in acute leukemias. The rearrangements are usually caused by chromosome translocations resulting in production of chimeric proteins composed of a segment of ALL-1 linked to a partner protein. In addition, a second type of ALL-1 linked to a partner protein. In addition, a second type of ALL-1 rearrangement was discovered in which N-terminal portion of the protein is tandemly repeated. ALL-1 is the human homologue of Drosophila trithorax (TRX) which plays an important roles in maintaining expression of homeotic genes during development. TRX is a member of the TRX-G family of genes. The products of some of these genes have been now shown to be components of multimeric protein complexes whose role is to open chromatin. Our recent studies indicate that ALL-1 too is present within a multi-meric protein complex. In the first part of the application, we propose to purify to homogeneity the multi-protein large complex containing normal ALL-1, and to subsequently determine whether the leukemogenic ALL-1 chimeric derivatives are also present within such a complex or within an altered version of it. In the second project, we propose to further study a novel gene, recently cloned by us, which is likely to correspond to the human homologue of Drosophila ash1. We will focus on generation of mice null for this gene, on characterization of the protein product and on attempts to determine whether the gene is involved in human cancer. In the final part of the application, on characterization of the protein product and on attempts to determine whether the gene is involved in human cancer. In the final part of the application, we propose to generate chimeric mice harboring the partially tandem duplicated ALL-1 and to determine whether mice develop leukemia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA050507-06A1
Application #
6403786
Study Section
Special Emphasis Panel (ZCA1)
Project Start
1994-07-01
Project End
2005-02-28
Budget Start
Budget End
Support Year
6
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Petruk, Svetlana; Black, Kathryn L; Kovermann, Sina K et al. (2013) Stepwise histone modifications are mediated by multiple enzymes that rapidly associate with nascent DNA during replication. Nat Commun 4:2841
Petruk, Svetlana; Sedkov, Yurii; Johnston, Danika M et al. (2012) TrxG and PcG proteins but not methylated histones remain associated with DNA through replication. Cell 150:922-33
Johnston, Danika M; Sedkov, Yurii; Petruk, Svetlana et al. (2011) Ecdysone- and NO-mediated gene regulation by competing EcR/Usp and E75A nuclear receptors during Drosophila development. Mol Cell 44:51-61
Petruk, Svetlana; Sedkov, Yurii; Brock, Hugh W et al. (2007) A model for initiation of mosaic HOX gene expression patterns by non-coding RNAs in early embryos. RNA Biol 4:1-6
Petruk, Svetlana; Sedkov, Yurii; Riley, Kristen M et al. (2006) Transcription of bxd noncoding RNAs promoted by trithorax represses Ubx in cis by transcriptional interference. Cell 127:1209-21
Krajewski, Wladyslaw A; Nakamura, Tatsuya; Mazo, Alexander et al. (2005) A motif within SET-domain proteins binds single-stranded nucleic acids and transcribed and supercoiled DNAs and can interfere with assembly of nucleosomes. Mol Cell Biol 25:1891-9
Canaani, E; Nakamura, T; Rozovskaia, T et al. (2004) ALL-1/MLL1, a homologue of Drosophila TRITHORAX, modifies chromatin and is directly involved in infant acute leukaemia. Br J Cancer 90:756-60
Smith, Sheryl T; Petruk, Svetlana; Sedkov, Yurii et al. (2004) Modulation of heat shock gene expression by the TAC1 chromatin-modifying complex. Nat Cell Biol 6:162-7
Petruk, Svetlana; Sedkov, Yurii; Smith, Sheryl T et al. (2004) Purification and biochemical properties of the Drosophila TAC1 complex. Methods Enzymol 377:255-66
Nakamura, Tatsuya; Mori, Toshiki; Tada, Shinichiro et al. (2002) ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol Cell 10:1119-28

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