Cancer Letters

Cancer Letters

Volume 197, Issues 1–2, 18 July 2003, Pages 87-92
Cancer Letters

Mini-review
The role of the MEIS homeobox genes in neuroblastoma

https://doi.org/10.1016/S0304-3835(03)00087-9Get rights and content

Abstract

We recently found amplification of the TALE homeobox gene MEIS1 in the IMR32 neuroblastoma cell line. We now demonstrate high-level expression of the MEIS1 and MEIS2 genes, as well as efficient expression of most other TALE family member genes in a panel of neuroblastoma cell lines. Stable transfection of MEIS1-expressing cell lines with cDNA encoding a naturally occurring dominant-negative splice variant of MEIS1 (MEIS1E) yielded clones with impaired cell proliferation, gain of differentiated phenotype, and increased contact inhibition and cell death. This indicated a relevance of MEIS expression for neuroblastoma cell growth and proliferation. We therefore determined the gene expression profiles of several MEIS1E transfectants using serial analysis of gene expression (SAGE). A large number of genes showed differential expression as a result of MEIS1E expression. These include genes involved in developmental signalling pathways, chromatin binding, cell cycle control, proliferation, and apoptosis. The results presented provide important clues for the oncogenic function of MEIS1 in neuroblastoma.

Section snippets

TALE gene expression in neuroblastoma

The neural crest-derived origin of the neuroblastoma tumour suggests involvement of key developmental regulator genes. We and others recently found amplification of the TALE homeobox gene MEIS1 in a neuroblastoma cell line, and demonstrated high expression of MEIS1 in many neuroblastoma cell lines, as well as in a number of neuroblastoma tumours [1], [2]. The homeobox genes constitute an important group of neural crest developmental regulators [3]. They encode transcription factors that bind to

Interference with MEIS1 function by expression of the MEIS1E dominant-negative variant

To determine the role of MEIS1 expression in neuroblastoma, and clarify the downstream targets of MEIS1, we decided to knock down MEIS1 function. We attempted this using a naturally occurring dominant-negative splice variant of MEIS proteins, called MEIS-E [22]. This MEIS variant cannot contribute to transcriptional regulation since it lacks the C-terminal part of the DNA-binding homeodomain. It can, however, still bind to other homeobox proteins like PBX, since this interaction is mediated

Gene expression profiles of the MEIS1E-transfected SJNB-8 cell line

We used SJNB-8 transfectants in SAGE, a high-throughput gene expression profiling method [23]. With SAGE, specific 10 nucleotide sequence fragments (‘tags’), each representing a single mRNA transcript, are cloned, sequenced, and counted. Typically, tags of highly expressed genes (e.g. ribosomal protein genes) are found 100 times or more per 100,000 tags, while tags of rare transcripts (like those of transcription factors) are found 1–10 times per 100,000 tags. Statistical analysis of the tag

Conclusion

The TALE homeobox genes are crucial for normal development of the nervous system, and are implicated in tumorigenesis. Most TALE subfamilies are widely expressed in a panel of neuroblastoma cell lines, suggesting the TALE transcriptional regulation is active in neuroblastoma. We have employed gene expression profiling on the SJNB-8 cell line using a dominant-negative MEIS1 splice variant. Many interesting putative MEIS1 target genes were identified. MEIS therefore seems to be an important

References (23)

  • T. Bürglin

    Analysis of TALE superclass homeobox genes (MEIS, PBX, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals

    Nucl. Acids Res.

    (1997)
  • Cited by (0)

    View full text