Alteration in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6/SHP1) may contribute to neutrophilic dermatoses.
ABSTRACT We have found a B2 repeat insertion in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6) in a mouse that developed a skin disorder with clinical and histopathological features resembling those seen in human neutrophilic dermatoses. Neutrophilic dermatoses are a group of complex heterogeneous autoinflammatory diseases that all demonstrate excessive neutrophil infiltration of the skin. Therefore, we tested the cDNA and genomic DNA sequences of PTPN6 from patients with Sweet's syndrome (SW) and pyoderma gangrenosum and found numerous novel splice variants in different combinations. Isoforms resulting from deletions of exons 2, 5, 11, and 15 and retention of intron 1 or 5 were the most common in a patients with a familial case of SW, who had a neonatal onset of an inflammatory disorder with skin lesions and a biopsy specimen consistent with SW. These isoforms were associated with a heterozygous E441G mutation and a heterozygous 1.7-kbp deletion in the promoter region of the PTPN6 gene. Although full-length PTPN6 was detected in all other patients with either pyoderma gangrenosum or SW, it was always associated with splice variants: a partial deletion of exon 4 with the complete deletion of exon 5, alterations that were not detected in healthy controls. The defect in transcriptional regulation of the hematopoietic PTPN6 appears to be involved in the pathogenesis of certain subsets of the heterogeneous group of neutrophilic dermatoses.
Article: Correlation between a single nucleotide polymorphism in the matrix metalloproteinase-2 promoter and risk of lung cancer.[show abstract] [hide abstract]
ABSTRACT: Matrix metalloproteinases (MMPs) play an important role in several steps of cancer development. A single nucleotide polymorphism (-1306C-->T) in the MMP2 promoter sequence disrupts an Sp1 site and thus results in strikingly lower promoter activity. We examined the relationship between this polymorphism and risk for lung cancer in 781 cases and 852 age- and sex-matched controls in a Chinese population. We found that the allele frequency of MMP2-1306C was significantly higher among cases than among controls (0.91 versus 0.83). Subjects with the CC genotype had an overall 2-fold increased risk for developing lung cancer [adjusted odds ratio (OR) 2.18; 95% confidence interval (CI), 1.70-2.79] compared with those with the CT or TT genotype. The elevated risk was observed evenly among different subtypes of this cancer. Stratified analysis indicated an additive interaction between the CC genotype and smoking on the elevated risk. The ORs of lung cancer for the CC genotype, smoking, and both factors combined were 2.38 (95% CI 1.64-3.45), 4.26 (95% CI 2.57-8.44), and 7.64 (95% CI 4.74-12.33), respectively. Furthermore, when the data were stratified by the pack-years smoked, this joint effect was more evident and stronger in heavy smokers (OR 10.25, 95% CI 5.80-18.09) than in light smokers (OR 5.55, 95% CI 3.34-9.22). These results demonstrate a significant association between the MMP2 -1306C/T polymorphism and risk of developing lung cancer solely or in a manner of interaction with carcinogen exposure.Cancer Research 11/2002; 62(22):6430-3. · 7.86 Impact Factor
Article: Mechanisms of SHP-1 P2 promoter regulation in hematopoietic cells and its silencing in HTLV-1-transformed T cells.[show abstract] [hide abstract]
ABSTRACT: The Src homology-2-containing protein-tyrosine phosphatase 1 (SHP-1), is a negative regulator of cell signaling. It is also considered a tumor suppressor gene because of its ability to antagonize the action of tyrosine kinases. Although SHP-1 is expressed strongly in hematopoietic cells, decreased expression has been observed in various hematological malignancies, which suggests a central involvement of SHP-1 in leukemogenesis. We have shown previously that human T cell lymphotropic virus type-1 (HTLV-1) Tax-induced promoter silencing (TIPS) is an early event causing down-regulation of SHP-1 expression, which is dependent on NF-kappaB. In this study, DNase I footprinting and EMSA also revealed binding of transcription factors, specificity protein 1 (Sp1) and octamer-binding transcription factor 1 (Oct-1) to the P2 promoter, and site-directed mutagenesis confirmed that these factors contribute to the basal P2 promoter activity. Chromatin immunoprecipitation (CHIP) assays showed that Sp1, Oct-1, NF-kappaB, CREB-1, and RNA polymerase II interacted with the core SHP-1 P2 promoter in CD4+ T cells and Jurkat cells but not in HTLV-1-transformed MT-2 and HUT102 cells when HTLV-1 Tax is present. Furthermore, bisulfite sequencing of the SHP-1 P2 core region revealed heavy CpG methylation in HTLV-1-transformed cells compared with freshly isolated CD4+ T cells and HTLV-1-noninfected T cell lines. A significant inverse correlation between degree of CpG methylation and expression of SHP-1 mRNA or protein was observed. Taken together, our data support the notion that in HTLV-1-transformed CD4+ T cells, TIPS causes dissociation of transcription factors from the core SHP-1 P2 promoter, which in turn leads to subsequent DNA methylation, an important early step for leukemogenesis.Journal of Leukocyte Biology 11/2008; 85(1):165-74. · 4.99 Impact Factor