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PMID: 17452456 Published · ppublish English Journal Article

Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis.

Molecular and cellular biology ·Vol. 27 ·No. 13 ·2007-07-00 ·Pages 4968-79

Wiederschain D, Chen L, Johnson B, Bettano K, Jackson D, Taraszka J, Wang YK, Jones MD, Morrissey M, Deeds J, Mosher R, Fordjour P, Lengauer C, Benson JD

Abstract

Bmi-1 and Mel-18 are structural homologues that belong to the Polycomb group of transcriptional regulators and are believed to stably maintain repression of gene expression by altering the state of chromatin at specific promoters. While a number of clinical and experimental observations have implicated Bmi-1 in human tumorigenesis, the role of Mel-18 in cancer cell growth has not been investigated. We report here that short hairpin RNA-mediated knockdown of either Bmi-1 or Mel-18 in human medulloblastoma DAOY cells results in the inhibition of proliferation, loss of clonogenic survival, anchorage-independent growth, and suppression of tumor formation in nude mice. Furthermore, overexpression of both Bmi-1 and Mel-18 significantly increases the clonogenic survival of Rat1 fibroblasts. In contrast, stable downregulation of Bmi-1 or Mel-18 alone does not affect the growth of normal human WI38 fibroblasts. Proteomics-based characterization of Bmi-1 and Mel-18 protein complexes isolated from cancer cells revealed substantial similarities in their respective compositions. Finally, gene expression analysis identified a number of cancer-relevant pathways that may be controlled by Bmi-1 and Mel-18 and also showed that these Polycomb proteins regulate a set of common gene targets. Taken together, these results suggest that Bmi-1 and Mel-18 may have overlapping functions in cancer cell growth.

MeSH Terms
Animals Cell Death Cell Proliferation Cell Survival DNA-Binding Proteins/genetics,metabolism Down-Regulation/genetics Fibroblasts/cytology Gene Expression Gene Expression Profiling Gene Expression Regulation, Neoplastic HeLa Cells Humans Medulloblastoma/genetics,pathology Mice Nuclear Proteins/genetics,metabolism Polycomb Repressive Complex 1 Polycomb-Group Proteins Proto-Oncogene Proteins/genetics,metabolism RNA, Small Interfering/metabolism Rats Repressor Proteins/chemistry,genetics,metabolism Sequence Homology, Amino Acid Transplantation, Heterologous
Chemicals
BMI1 protein, human DNA-Binding Proteins Nuclear Proteins PCGF2 protein, human Polycomb-Group Proteins Proto-Oncogene Proteins RNA, Small Interfering Repressor Proteins Polycomb Repressive Complex 1
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Wiederschain Dmitri
Oncology Research, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
Chen Lin
Johnson Brett
Bettano Kimberly
Jackson Dowdy
Taraszka John
Wang Y Karen
Jones Michael D
Morrissey Michael
Deeds James
Mosher Rebecca
Fordjour Paul
Lengauer Christoph
Benson John D
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.02244-06
Published
2007-07-00
Epub
2007-00-23
Pages
4968-79
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1951487
Subset
IM
Databases
GEO
GSE7578
External Links
PubMed source DOI: 10.1128/MCB.02244-06 PMC Full Text View journal details
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