Analysis of the complex genomic structure of Bcl-x and its relationship to Bcl-x(gamma) expression after CD28-dependent costimulation.
ABSTRACT The Bcl-x(gamma) cytosolic protein is essential for costimulatory activity after CD3/CD28 coligation. Here we delineate the Bcl-x(gamma)/Bcl-x genomic organization and the molecular mechanism that allows expression. We show that exon 4 of the Bcl-x gene encodes the unique C-terminal end of the Bcl-x(gamma) molecule while exons 5, 6, 7 and 8 are differentially transcribed to yield three alternative Bcl-x(gamma) 3' untranslated regions (UTR). CD28-dependent signals may increase levels of Bcl-x(gamma) protein through induction of an alternatively-spliced Bcl-x(gamma) 3' UTR that contains stem loop structures that stabilize Bcl-x(gamma) RNA. The ability receptor-induced signals to regulate the splicing pattern of the complex Bcl-x gene may allow T-cells to respond appropriately to antigenic stimuli.
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ABSTRACT: We report the isolation of bcl-x, a bcl-2-related gene that can function as a bcl-2-independent regulator of programmed cell death (apoptosis). Alternative splicing results in two distinct bcl-x mRNAs. The protein product of the larger mRNA, bcl-xL, is similar in size and predicted structure to Bcl-2. When stably transfected into an IL-3-dependent cell line, bcl-xL inhibits cell death upon growth factor withdrawal at least as well as bcl-2. Surprisingly, the second mRNA species, bcl-xS, encodes a protein that inhibits the ability of bcl-2 to enhance the survival of growth factor-deprived cells. In vivo, bcl-xS mRNA is expressed at high levels in cells that undergo a high rate of turnover, such as developing lymphocytes. In contrast, bcl-xL is found in tissues containing long-lived postmitotic cells, such as adult brain. Together these data suggest that bcl-x plays an important role in both positive and negative regulation of programmed cell death.Cell 09/1993; 74(4):597-608. · 31.96 Impact Factor
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ABSTRACT: Representational difference analysis was used to search for pathogens in multiple sclerosis brains. We detected a 341-nucleotide fragment that was 99.4% identical to the major DNA binding protein gene of human herpesvirus 6 (HHV-6). Examination of 86 brain specimens by PCR demonstrated that HHV-6 was present in > 70% of MS cases and controls and is thus a commensal virus of the human brain. By DNA sequencing, 36/37 viruses from MS cases and controls were typed as HHV-6 variant B group 2. Other herpesviruses, retroviruses, and measles virus were detected infrequently or not at all. HHV-6 expression was examined by immunocytochemistry with monoclonal antibodies against HHV-6 virion protein 101K and DNA binding protein p41. Nuclear staining of oligodendrocytes was observed in MS cases but not in controls, and in MS cases it was observed around plaques more frequently than in uninvolved white matter. MS cases showed prominent cytoplasmic staining of neurons in gray matter adjacent to plaques, although neurons expressing HHV-6 were also found in certain controls. Since destruction of oligodendrocytes is a hallmark of MS, these studies suggest an association of HHV-6 with the etiology or pathogenesis of MS.Proceedings of the National Academy of Sciences 08/1995; 92(16):7440-4. · 9.74 Impact Factor
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ABSTRACT: Langerhans cells (LC) appear to have a role in the processing of antigens presented through cutaneous surfaces. In most species LC are found in the conjunctiva and limbal epithelium but are rarely found in the central cornea. A quantitative study of corneal LC was performed in guinea pigs and rabbits with HSV-1 keratitis. Corneal epithelial sheets were removed, stained with ATPase and counted in the peripheral, paracentral and central cornea. Results in guinea pigs showed statistically significant increases of LC on days 6, 16, 21 and 28 in the paracentral and central cornea of HSV eyes. Results in rabbits showed an increase in LC on days 9, 13 and 21 in the paracentral and central cornea of HSV eyes. No LC were found in the central cornea of control eyes. The results indicate a migration of LC to the central cornea as a result of HSV keratitis.Current Eye Research 02/1987; 6(1):179-82. · 1.71 Impact Factor