Mini-reviewThe role of the MEIS homeobox genes 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)
- et al.
The homeobox gene MEIS1 is amplified in IMR-32 and highly expressed in other neuroblastoma cell lines
Eur. J. Cancer
(2000) - et al.
The MEIS1 oncogene is highly expressed in neuroblastoma and amplified in cell line IMR32
Genomics
(2001) Hox genes in vertebrate development
Cell
(1994)- et al.
Inhibition of myeloid differentiation by Hoxa9, Hoxb8, and Meis homeobox genes
Exp. Hematol.
(2001) - et al.
Control of vertebrate limb outgrowth by the proximal factor Meis2 and distal antagonism of BMPs by gremlin
Mol. Cell
(1999) - et al.
Amplification and overexpression of TGIF2, a novel homeobox gene of the TALE superclass, in ovarian cancer cell lines
Biochem. Biophys. Res. Commun.
(2000) - et al.
Identification and characterization of human PKNOX2, a novel homeobox-containing gene
Biochem. Biophys. Res. Commun.
(2001) - et al.
Three-amino acid extension loop homeodomain proteins Meis2 and TGIF differentially regulate transcription
J. Biol. Chem.
(2000) - et al.
Homeobox genes in normal and malignant cells
J. Cell. Physiol.
(2001) - et al.
Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins
Genes Dev.
(1995)