E2F1 induces cell death, calpain activation, and MDMX degradation in a transcription independent manner implicating a novel role for E2F1 in neuronal loss in SIV encephalitis.
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 lysosomal 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 a new function for E2F1 in the activation of calpain proteases and suggest a role for this pathway in SIVE.
Strachan
Gordon D
GD
Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6030, USA.
Koike
Maya A
MA
Siman
Robert
R
Hall
David J
DJ
Jordan-Sciutto
Kelly L
KL
D000818:Animals; D002154:Calpain / Q000378:metabolism*; D002453:Cell Cycle; D016923:Cell Death; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D004660:Encephalitis / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D004789:Enzyme Activation; D005434:Flow Cytometry; D017930:Genes, Reporter; D008253:Macaca mulatta; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000473:pathology*; D011499:Protein Processing, Post-Translational; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53
D050687:E2F1 Transcription Factor; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D002154:Calpain