Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.60 (caspase-7)
 920 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytotoxic T lymphocytes (CTLs) and natural killers (NK) cells provide immune surveillance against viruses and neoplasms, and play a central role in the pathogenesis of autoimmune disease, AIDS and graft rejection. Thus, it is important to understand the precise molecular mechanism(s) whereby cytotoxic lymphocytes destroy susceptible target cells. Granule-mediated cytotoxicity requires a combination of both perforin and granzyme B. Perforin polymerizes to form transmembrane channels and presumably allows granzyme B access to target cell substrates, which until recently, were unknown. One clue to the identity of the physiological substrate(s) activated by granzyme B comes from its unusual specificity for cleaving synthetic substrates after aspartate residues. Members of the ICE/CED-3 family of cysteine proteases are prime candidates as they are important apoptotic effectors and are expressed as zymogens, which can be processed to form active heterodimeric enzymes after cleavage at specific aspartate residues. Previous studies have shown that granzyme B proteolytically activates the cell death effector Yama/CPP32/apopain (referred to here as Yama). Here we report that granzyme B also activates ICE-LAP3/Mch3/CMH-1 (referred to here as ICE-LAP3), which, along with Yama and Mch2, forms a subset of the ICE/CED-3 family of cysteine proteases most closely related to the Caenorhabditis elegans cell death gene, CED-3. Importantly, Jurkat T cells incubated with granzyme B and a sublytic concentration of perforin undergo apoptosis, which is preceded by the activation of endogenous ICE-LAP3. Thus, we propose that granzyme B mediates apoptosis by directly engaging the target cell's death effector machinery, which is probably composed of an arsenal of intracellular, CED-3-like cysteine proteases.
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PMID:Cytotoxic T-cell-derived granzyme B activates the apoptotic protease ICE-LAP3. 880 7

Apoptosis is a cell death program involved in the development of multicellular organisms, immunity, and pathologies ranging from cancer to HIV/AIDS. We present an engineered protein that causes rapid apoptosis of targeted cells in monolayer culture after stimulation with blue light. Cells transfected with the protein switch L57V, a tandem fusion of the light-sensing LOV2 domain and the apoptosis-executing domain from caspase-7, rapidly undergo apoptosis within 60 min after light stimulation. Constant illumination of under 5 min or oscillating with 1 min exposure had no effect, suggesting that cells have natural tolerance to a short duration of caspase-7 activity. Furthermore, the overexpression of Bcl-2 prevented L57V-mediated apoptosis, suggesting that although caspase-7 activation is sufficient to start apoptosis, it requires mitochondrial contribution to fully commit.
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PMID:Engineering a photoactivated caspase-7 for rapid induction of apoptosis. 2365 Oct 71

Selenium compounds such as methylseleninic acid (MSA) and sodium selenite (SS) have been widely evaluated as potential anti-cancer agents in the clinical setting. Primary effusion lymphoma (PEL) is a non-Hodgkin's B-cell lymphoma, associated with immunosuppressed individuals, such as post-transplant or AIDS patients. Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of PEL and Kaposi's sarcoma. Here, we found that MSA and SS markedly inhibited the growth of PEL cells compared with KSHV-uninfected B cells. MSA and SS caused ER stress, inducing the unfolded protein response (UPR) pathway in PEL cells that resulted in pro-apoptotic UPR, and finally apoptosis. The expression of UPR-related molecules (GRP78 and GADD34) and pro-apoptotic UPR molecules (CHOP, Bim, or Puma) were augmented in PEL cells treated with MSA or SS. In addition, these compounds induced the activation of caspase-4, an ER stress specific caspase, as well as caspase-3,-7, and -9 in PEL cells. We confirmed that thapsigargin which is an inducer of ER stress, dramatically decreased the viability of PEL cells, compared with KSHV-uninfected Ramos cells. We also investigated whether MSA or SS caused oxidization of cellular proteins in PEL cells. MSA and SS increased the levels of oxidative proteins in PEL cells, and the anti-oxidant agent (N-acetyl-l-cysteine) restored cell viability and suppressed caspase-7 activation in PEL cells treated with MSA or SS. Finally, we confirmed that MSA and SS induced neither lytic replication nor viral production in PEL cells. Taken together, MSA and SS could serve as lead compounds for the development of novel and effective drugs against PEL without the risk of de novo KSHV production.
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PMID:Methylseleninic acid and sodium selenite induce severe ER stress and subsequent apoptosis through UPR activation in PEL cells. 2816 10