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PMID: 17178841 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth.

Molecular and cellular biology ·Vol. 27 ·No. 5 ·2007-03-00 ·Pages 1889-903

Issaeva I, Zonis Y, Rozovskaia T, Orlovsky K, Croce CM, Nakamura T, Mazo A, Eisenbach L, Canaani E

Abstract

ALR (MLL2) is a member of the human MLL family, which belongs to a larger SET1 family of histone methyltransferases. We found that ALR is present within a stable multiprotein complex containing a cohort of proteins shared with other SET1 family complexes and several unique components, such as PTIP and the jumonji family member UTX. Like other complexes formed by SET1 family members, the ALR complex exhibited strong H3K4 methyltransferase activity, conferred by the ALR SET domain. By generating ALR knockdown cell lines and comparing their expression profiles to that of control cells, we identified a set of genes whose expression is activated by ALR. Some of these genes were identified by chromatin immunoprecipitation as direct ALR targets. The ALR complex was found to associate in an ALR-dependent fashion with promoters and transcription initiation sites of target genes and to induce H3K4 trimethylation. The most characteristic features of the ALR knockdown cells were changes in the dynamics and mode of cell spreading/polarization, reduced migration capacity, impaired anchorage-dependent and -independent growth, and decreased tumorigenicity in mice. Taken together, our results suggest that ALR is a transcriptional activator that induces the transcription of target genes by covalent histone modification. ALR appears to be involved in the regulation of adhesion-related cytoskeletal events, which might affect cell growth and survival.

MeSH Terms
Animals Apoptosis/genetics Cell Adhesion/genetics Cell Movement/genetics Cell Proliferation Chromatin Immunoprecipitation DNA-Binding Proteins/genetics,isolation & purification Gene Expression Profiling HeLa Cells Histone Methyltransferases Histone-Lysine N-Methyltransferase/metabolism Humans K562 Cells Methylation Mice Mice, Nude Neoplasm Proteins/genetics,isolation & purification Neoplasm Transplantation Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic Protein Methyltransferases Protein Structure, Tertiary Reverse Transcriptase Polymerase Chain Reaction Time Factors Transcription, Genetic Tumor Burden
Chemicals
DNA-Binding Proteins KMT2D protein, human Neoplasm Proteins Histone Methyltransferases Protein Methyltransferases Histone-Lysine N-Methyltransferase
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Issaeva Irina
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Zonis Yulia
Rozovskaia Tanya
Orlovsky Kira
Croce Carlo M
Nakamura Tatsuya
Mazo Alex
Eisenbach Lea
Canaani Eli
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.01506-06
Published
2007-03-00
Epub
2006-00-18
Pages
1889-903
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1820476
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.01506-06 PMC Full Text View journal details
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