Biochemical and biophysical research communications
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Biochem. Biophys. Res. Commun. · Dec 2005
ReviewThe von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing.
The heterodimeric transcription factor HIF (hypoxia-inducible factor), consisting of a labile alpha-subunit and a stable beta-subunit, is a master regulator of genes involved in acute or chronic adaptation to low oxygen. Studies performed over the past 5 years revealed that HIFalpha-subunits are enzymatically hydroxylated in an oxygen-dependent manner. Hydroxylation of either of two conserved prolyl residues targets HIFalpha for destruction by a ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein whereas hydroxylation on a C-terminal asparagine affects HIF transactivation function. Pharmacological manipulation of HIF activity might be beneficial in diseases characterized by abnormal tissue oxygenation including myocardial infarction, cerebrovascular disease, and cancer.
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Angiogenesis is a complex process that is regulated by a variety of angiogenic activators and inhibitors. Disruption of the balanced angiogenesis leads to the progress of diseases such as tumor growth, rheumatoid arthritis, and various blood vessel-related disorders. Even though a number of proteins involved in angiogenesis have been identified so far, more protein factors remain to be identified due to complexity of the process. ⋯ High level of vascular endothelial growth factor (VEGF), a prominent angiogenic factor, is also detected in conditioned medium obtained from cells transfected with ANXA3 expression plasmid. Reporter assays show that ANXA3 enhances hypoxia-inducible factor-1 (HIF-1) transactivation activity. Taken together, our results suggest that ANXA3 is a novel angiogenic factor that induces VEGF production through the HIF-1 pathway.
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Biochem. Biophys. Res. Commun. · Nov 2005
Selective silencing of a mutant transthyretin allele by small interfering RNAs.
Familial amyloidotic polyneuropathy (FAP) is a hereditary systemic amyloidosis caused by dominantly acting missense mutations in the gene encoding transthyretin (TTR). The most common mutant TTR is of the Val30Met type, which results from a point mutation. ⋯ We have identified an siRNA that specifically inhibits mutant, but not wild-type, TTR expression even in cells expressing both alleles. Thus, this siRNA-based approach may have potential for the gene therapy of FAP.
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Biochem. Biophys. Res. Commun. · Oct 2005
Differential tyrosine phosphorylation of leukemic cells during apoptosis as a result of treatment with imatinib mesylate.
Bcr-Abl fusion tyrosine kinase contributes to leukemic transformation. Imatinib mesylate inhibits Bcr-Abl tyrosine kinase, resulting in a blockage of tyrosine phosphorylation in its downstream pathways. We analyzed the alteration of tyrosine phosphorylation, on BCR/ABL+ chronic myelogenous leukemia cells, after treatment with imatinib mesylate. ⋯ Ten of the 24 protein spots are visible at all three times. Four are detectable at both the 0 and 24 h points in time. Eight were detectable only at time 0.
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Biochem. Biophys. Res. Commun. · Oct 2005
Clinical Trial Controlled Clinical TrialThe influence of HER2 genotypes as molecular markers in ovarian cancer outcome.
A relevant clinical problem in the treatment of ovarian cancer (OC) is the development of resistance to chemotherapy, frequently due to genetic variations in enzymes and receptors. Changes in the HER2 receptor have been associated with breast and ovarian cancers. The role of a polymorphism in the HER2 gene in the clinical outcome of OC patients was investigated in this study. ⋯ Our results indicate that patients carrying the valine homozygotic genotype present a lower overall survival mean, suggesting a role for this polymorphism in the outcome of ovarian cancer patients. The G allele has been implicated in the formation of active HER2 receptors, with a more aggressive phenotype. We hypothesize that HER2 genotypes can be predictive biomarkers in ovarian cancer, contributing to a genetic individual profile of great interest in clinical oncology.