Abstract:The adenovirus E1A oncogene induces innate immune rejection of tumors by sensitizing tumor cells to apoptosis in response to injuries, such as those inflicted by macrophage-produced TNF α and NO. E1A sensitizes cells to TNF by repressing its activation of NF-κB-dependent, antiapoptotic defenses. This suggested the hypothesis that E1A blockade of the NF-κB activation response might be the central mechanism of E1A induced cellular sensitivity to other proapoptotic injuries, such as macrophage-produced NO. Howeve… Show more
“…More recent data have provided additional evidence that caspase-2 influences the cell cycle. MEFs derived from caspase-2 knockout mice proliferated substantially faster than wild type cells [58], an effect that was exaggerated in MEF lines transformed with the oncogenes E1A (which promotes caspase-2 upregulation [25]) and Ras [58]. As discussed above, caspase-2 knockout mice develop normally [19,55] and transplantation of foetal liver cells from knockout and normal mice into irradiated recipients yielded equivalent cellularity in haemopoietic compartments [65].…”
Section: Biological Role(s) Of Caspase-2mentioning
confidence: 91%
“…Interestingly, caspase-1 has also been implicated in lipid synthesis, through indirect induction of SREBP processing and activation [24]. Expression Calculated using the protein-protein basic local alignment search tool (BLAST) [179,180] relative to CED-3 (NP_502538) of the adenoviral oncogene E1A boosted levels of caspase-2 protein in murine (but not human) fibroblasts, through an unknown mechanism [25]. It was recently reported that p53 and p73 could repress caspase-2 mRNA and protein expression, in a p21-dependent manner [26].…”
The caspases are an evolutionarily conserved family of cysteine proteases, with essential roles in apoptosis or inflammation. Caspase-2 was the second caspase to be cloned and it resembles the prototypical nematode caspase CED-3 more closely than any other mammalian protein. An absence of caspase-2-specific reagents and the subtle phenotype of caspase-2-deficient mice have hampered definition of the physiological role of caspase-2 and identification of factors regulating its activity. Although some data implicate caspase-2 in apoptotic pathways, a link with apoptosis has been less firmly established for caspase-2 than for some other caspases. Emerging evidence suggests that caspase-2 regulates the cell cycle and may act as a tumour suppressor. This article critically reviews the current state of knowledge regarding the biochemistry and biology of this controversial caspase.
“…More recent data have provided additional evidence that caspase-2 influences the cell cycle. MEFs derived from caspase-2 knockout mice proliferated substantially faster than wild type cells [58], an effect that was exaggerated in MEF lines transformed with the oncogenes E1A (which promotes caspase-2 upregulation [25]) and Ras [58]. As discussed above, caspase-2 knockout mice develop normally [19,55] and transplantation of foetal liver cells from knockout and normal mice into irradiated recipients yielded equivalent cellularity in haemopoietic compartments [65].…”
Section: Biological Role(s) Of Caspase-2mentioning
confidence: 91%
“…Interestingly, caspase-1 has also been implicated in lipid synthesis, through indirect induction of SREBP processing and activation [24]. Expression Calculated using the protein-protein basic local alignment search tool (BLAST) [179,180] relative to CED-3 (NP_502538) of the adenoviral oncogene E1A boosted levels of caspase-2 protein in murine (but not human) fibroblasts, through an unknown mechanism [25]. It was recently reported that p53 and p73 could repress caspase-2 mRNA and protein expression, in a p21-dependent manner [26].…”
The caspases are an evolutionarily conserved family of cysteine proteases, with essential roles in apoptosis or inflammation. Caspase-2 was the second caspase to be cloned and it resembles the prototypical nematode caspase CED-3 more closely than any other mammalian protein. An absence of caspase-2-specific reagents and the subtle phenotype of caspase-2-deficient mice have hampered definition of the physiological role of caspase-2 and identification of factors regulating its activity. Although some data implicate caspase-2 in apoptotic pathways, a link with apoptosis has been less firmly established for caspase-2 than for some other caspases. Emerging evidence suggests that caspase-2 regulates the cell cycle and may act as a tumour suppressor. This article critically reviews the current state of knowledge regarding the biochemistry and biology of this controversial caspase.
“…In addition, the E1a antitumor effect may be involved in many genetic factors in cancer cells, including E1a-induced apoptosis (Radke et al, 2008), Ela-enhanced sensitivity to chemotherapeutics and radiation (Sánchez-Prieto et al, 1996), E1a-triggered accumulation of p53 product and the E1a-mediated down-regulation of the oncogene Neu (ErbB-2/HER2) expression (Bartholomeusz et al, 2005;Madhusudan et al, 2004). Neu protein is a member of epidermal growth factor receptor (EGFR) and is commonly overexpressed in many human solid cancers, eg.…”
Section: Modification Of Adenovirus E1a Gene For Cradsmentioning
“…Unfixed corpses were collected and prepared for flow cytometry by washing in PBS ϩ 3% FBS and staining with Hoechst dye and propidium iodide (PI) (14). Externalization of phosphatidylserine residues on the outer plasma membranes of apoptotic cells was assayed by staining CPE corpses with anti-annexin V antibody and 7-amino actinomycin D (7-AAD) according to the manufacturer's recommendations (BD Pharmingen).…”
Section: E Ukaryotic Cells Undergo Different Types Of Cell Death Respmentioning
Cells that undergo apoptosis in response to
innate immune inflammation during accumulation of virally infected cells at sites of infection and suggest that E1B 19K-deleted, replicating adenoviral vectors might induce greater inflammatory responses to virally infected cells than E1B 19K-positive vectors, because of the net effect of their loss-of-function mutation.
IMPORTANCE
We observed that cells dying a nonapoptotic cell death induced by adenovirus infection repressed macrophage proinflammatory responses while cells dying by apoptosis induced by infection with an E1B 19K deletion mutant virus did not repress macro-
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