The Bcl-2 family of proteins plays a critical role in controlling immune responses by regulating the expansion and contraction of activated lymphocyte clones by apoptosis. ABT-737, which was originally developed for oncology, is a potent inhibitor of Bcl-2, Bcl-x(L), and Bcl-w protein function. There is evidence that Bcl-2-associated dysregulation of lymphocyte apoptosis may contribute to the pathogenesis of autoimmunity and lead to the development of autoimmune diseases.
View Article and Find Full Text PDFThe MEK kinase TPL-2 (also known as Cot) is required for lipopolysaccharide (LPS) activation of the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase cascade in macrophages and consequent upregulation of genes involved in innate immune responses. In resting cells, TPL-2 forms a stoichiometric complex with NF-kappaB1 p105, which negatively regulates its MEK kinase activity. Here, it is shown that lipopolysaccharide (LPS) stimulation of primary macrophages causes the release of both long and short forms of TPL-2 from p105 and that TPL-2 MEK kinase activity is restricted to this p105-free pool.
View Article and Find Full Text PDFInterferon-gamma-inducing factor (IGIF, interleukin-18) is a recently described cytokine that shares structural features with the interleukin-1 (IL-1) family of proteins and functional properties with IL-12. Like IL-12, IGIF is a potent inducer of interferon (IFN)-gamma from T cells and natural killer cells. IGIF is synthesized as a biologically inactive precursor molecule (proIGIF).
View Article and Find Full Text PDFRecent studies have shown that protein kinase C (PKC) delta is proteolytically activated at the onset of apoptosis induced by DNA-damaging agents, tumor necrosis factor, and anti-Fas antibody. However, the relationship of PKC delta cleavage to induction of apoptosis is unknown. The present studies demonstrate that full-length PKC delta is cleaved at DMQD330N to a catalytically active fragment by the cysteine protease CPP32.
View Article and Find Full Text PDFThe Caenorhabditis elegans cell death gene, ced-3, encodes one of the two proteins required for apoptosis in this organism. The primary sequence similarities between Ced-3 and the mammalian interleukin-1beta converting enzyme (ICE) suggest that these two proteins may have functionally similar active sites and that Ced-3 may function as a cysteine protease. Here we report that in vitro transcribed and translated Ced-3 protein (p56) underwent rapid processing to smaller fragments.
View Article and Find Full Text PDFThe baculovirus antiapoptotic protein p35 inhibited the proteolytic activity of human interleukin-1 beta converting enzyme (ICE) and three of its homologs in enzymatic assays. Coexpression of p35 prevented the autoproteolytic activation of ICE from its precursor form and blocked ICE-induced apoptosis. Inhibition of enzymatic activity correlated with the cleavage of p35 and the formation of a stable ICE-p35 complex.
View Article and Find Full Text PDFInterleukin-1 beta converting enzyme (ICE) is a cytoplasmic cysteine protease required for generating the bioactive form of the interleukin-1 beta cytokine from its inactive precursor. We report the identification of ICH-2, a novel human gene encoding a member of the ICE cysteine protease family, and characterization of its protein product. ICH-2 mRNA is widely expressed in human tissues in a pattern similar to, but distinct from, that of ICE.
View Article and Find Full Text PDFTerminal deoxynucleotidyl transferase (TdT) is a template-independent DNA polymerase that is transiently expressed during the normal development of T and B lymphocytes. Phorbol 12-myristate 13-acetate (PMA) has been reported to induce maturation-like changes, including the loss of TdT, in many leukemic cell lines. We investigated the mechanism of TdT repression by PMA in an early thymocyte-like cell line, RPMI 8402.
View Article and Find Full Text PDFJ Acquir Immune Defic Syndr (1988)
March 1989
In order to improve understanding of how HIV-1 infection down-modulates cell surface membrane expression of CD4, we have measured several parameters of CD4 expression in the human tumor T-cell lines CEM and MOLT-4 at different times after infection. Three independent HIV-1 isolates were used including one that encodes a truncated nef protein and another that appeared to be noncytolytic against CEM. The level of CD4 mRNA, the rate of biosynthesis of CD4 protein, and the percentage of CD4-positive cells were measured.
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