Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 96, Issue 4, Pages 728-740Publisher
WILEY
DOI: 10.1002/jcb.20574
Keywords
necrosis; apoptosis; E2F1; SIV; encephalitis; cell cycle; neurodegeneration; calpain; protease; lysosome
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The E2F1 transcription factor can initiate proliferation or apoptosis, the latter by both transcription-dependent and -independent mechanisms. Recently, an E2F1 mutant lacking the DNA binding domain, E2F1 (180-437), has been implicated in degradation of MDMX and MDM2 proteins via lysosomai proteases. MDM proteins block p53 dependent apoptosis by directly inhibiting p53 stability and function. Here we demonstrate E2F1 (180-437) induces death in HEK293 cells independent of E2F1 transcriptional activation and p53 stabilization. E2F1 (180-437) elevates the activity of the calcium-activated protease, calpain, which is required for E2F1 induced proteolysis of MDMX and E2F1 induced cell loss. To determine if E2F1 could be activating proteolysis via calpains in neurodegeneration, we examined MDMX immunofluorescence in simian immunodeficiency virus encephalitis (SIVE). We found a reciprocal relationship between E2F1 and MDMX staining: in SIVE where E2F1 immunostaining is increased, MDMX is decreased, while in controls where E2F1 immunostaining is low, MDMX is high. Together these experiments support anew function for E2F1 in the activation of calpain proteases and suggest a role for this pathway in SIVE.
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