An analysis of PAX1 in the development of vertebral malformations. Due to the sporadic occurrence of congenital vertebral malformations, traditional linkage approaches to identify genes associated with human vertebral development are not possible. We therefore identified PAX1 as a candidate gene in vertebral malformations and congenital scoliosis due to its mutation in the undulated mouse. We performed DNA sequence analysis of the PAX1 gene in a series of 48 patients with congenital vertebral malformations, collectively spanning the entire vertebral column length. DNA sequence coding variants were identified in the heterozygous state in exon 4 in two male patients with thoracic vertebral malformations. One patient had T9 hypoplasia, T12 hemivertebrae and absent T10 pedicle, incomplete fusion of T7 posterior elements, ventricular septal defect, and polydactyly. This patient had a CCC (Pro)-->CTC (Leu) change at amino acid 410. This variant was not observed in 180 chromosomes tested in the National Institute of Environmental Health Sciences (NIEHS) single nucleotide polymorphism (SNP) database and occurred at a frequency of 0.3% in a diversity panel of 1066 human samples. The second patient had a T11 wedge vertebra and a missense mutation at amino acid 413 corresponding to CCA (Pro)-->CTA (Leu). This particular variant has been reported to occur in one of 164 chromosomes in the NIEHS SNP database and was found to occur with a similar frequency of 0.8% in a diversity panel of 1066 human samples. Although each patient's mother was clinically asymptomatic and heterozygous for the respective variant allele, the possibility that these sequence variants have clinical significance is not excluded.
Recent reports have demonstrated that the HIV-1 transactivator protein, tat, induces apoptosis in T-lymphocyte cell lines, as well as in peripheral blood mononuclear cells, and stimulates a cascade of events resulting in up-regulation of the potent immunosuppressive cytokine, transforming growth factor-beta (TGF-beta). In this study we evaluated the ability of TGF-beta to mediate tat induced apoptosis in T-lymphocyte cell lines. T-cells treated exogenously with either TGF-beta1 or a combination of tat and pan-specific TGF-beta neutralizing antibodies showed little change in the amount of apoptosis. When treated with pan-specific TGF-beta neutralizing antibodies, Jurkat cells that stably express tat protein (Jurkat-tat ) showed only a modest decrease in apoptosis, while CEM-TART cells (CEM T-cells expressing both HIV-1 tat and rev ) demonstrated little change in the amount of apoptosis. In conclusion, we have demonstrated that TGF-beta does not play a significant role in mediating tat induced T-cell apoptosis.
Homeobox (HOX) genes are crucial regulators of cell growth and differentiation. These genes initiate and control gene expression cascades that drive development. More recently, the absent or aberrant expression of HOX genes has been implicated in cancer development. Despite the observance of these expression changes, the regulation of the HOX genes in adult tissues and how these genes become deregulated in cancerous tissues still needs much investigation. We characterized the promoter region of the HOXB13 gene. A 3 kb region upstream of the HOXB13 gene, which included the 5'UTR, increased reporter gene expression in LNCaP cells by approximately 99 fold over the promoterless control construct. A highly conserved 179 base pair fragment containing only the 5'UTR of the HOXB13 gene constituted a minimal promoter in the LNCaP cell line. Strong promoter activity was seen in the presence or absence of testosterone, although testosterone exposure did decrease expression in LNCaP cells by 50%. In an androgen insensitive cell line Du145, no sensitivity to testosterone was detected and a consistent low basal level of expression was observed. Since HOXB13 expression is highly tissue specific, we investigated the ability of the promoter to drive expression in tissues other than prostate. We observed highest expression in LNCaP cells with low levels of expression in lung, retinoblastoma, and colon cancer cells and higher expression in MCF7 breast cancer cells.
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