RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia
Open Access
- 1 September 2000
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 9 (15) , 2297-2304
- https://doi.org/10.1093/oxfordjournals.hmg.a018921
Abstract
The SH2 domain-containing tyrosine phosphatase PTPN6 (SHP-1, PTP1C, HCP) is a 68 kDa cytoplasmic protein primarily expressed in hematopoietic cell development, proliferation and receptor-mediated mitogenic signaling pathways. By means of direct dephosphorylation, it down-regulates a broad spectrum of growth-promoting receptors, including the Kit tyrosine kinase, activated to elicit a prominent cascade of intracellular events by stem cell factor binding. The pivotal contribution of PTPN6 in modulating myeloid cell signaling has been revealed by the finding that shp-1 mutation is responsible for the overexpansion and inappropriate activation of myelomonocytic populations in motheaten (me/me) and motheaten viable(mev/mev) mice. Association of PTPN6 with c-Kit and negative modulation of the myeloid leukocyte signal transduction pathways prompted us to examine the expression of the protein tyrosine phosphatase PTPN6 gene in CD34+/CD117+ blasts from acute myeloid leukemia patients. We identified and cloned cDNAs representing novel PTPN6 mRNA species, derived from aberrant splicing within the N-SH2 domain leading to retention of intron 3. Sequence analysis of cDNA clones revealed multiple A→G editing conversions. The editing of PTPN6 mRNA mainly occurred as an A→G conversion of A7866, which represents the putative branch site in IVS3 of PTPN6 mRNA. Evidence that editing of A7866 abrogates splicing has been obtained in vitro by using an edited clone and its backward clone generated by site-directed mutagenesis. The level of the aberrant intron-retaining splice variant, evaluated by semi-quantitative RT–PCR, was lower in CD117+-AML bone marrow mononuclear cells at remission than at diagnosis, suggesting the involvement of post-transcriptional PTPN6 processing in leukemogenesis.Keywords
This publication has 40 references indexed in Scilit:
- Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formationThe EMBO Journal, 1998
- Evidence that translation reinitiation abrogates nonsense-mediated mRNA decay in mammalian cellsThe EMBO Journal, 1997
- Genetic analysis reveals cell type-specific regulation of receptor tyrosine kinase c-Kit by the protein tyrosine phosphatase SHP1.The Journal of Experimental Medicine, 1996
- Signalling by the W/Kit receptor tyrosine kinase is negatively regulated in vivo by the protein tyrosine phosphatase Shp1Nature Genetics, 1996
- Human Protein Tyrosine Phosphatase 1C (PTPN6) Gene Structure: Alternate Promoter Usage and Exon Skipping Generate Multiple TranscriptsGenomics, 1995
- The MATK Tyrosine Kinase Interacts in a Specific and SH2-dependent Manner with c-KitPublished by Elsevier ,1995
- Editing of glutamate receptor subunit B pre-mRNA in vitro by site-specific deamination of adenosineNature, 1995
- Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signalsCell, 1995
- Expression and catalytic activity of the tyrosine phosphatase PTP1C is severely impaired in motheaten and viable motheaten mice.The Journal of Experimental Medicine, 1993
- Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase geneNature Genetics, 1993