Regulation of the retinoblastoma-dependent Mdm2 and E2F-1 signaling pathways during neuronal apoptosis.
We have previously demonstrated that the apoptotic signaling pathway in K(+)-deprived cerebellar granule neurons involves a caspase-dependent cleavage of the retinoblastoma protein (Rb). Here, we have further investigated the functional consequences of this cleavage on two Rb-binding partners: the oncoprotein Mdm2 and the transcription factor E2F-1. A K(+) deprivation time course leads to a caspase inhibitor-sensitive degradation of Mdm2. Experimental blockade of Mdm2 expression with antisense oligodeoxynucleotides (ODN) results in neuronal death, suggesting an active role of Mdm2 in neuroprotection. By contrast, the E2F-1 protein accumulates in a caspase-independent manner following K(+) withdrawal, a consequence of increased gene transcription. This is likely to result from the rapid cyclin-dependent kinase 4 activation observed in LK, that correlates with a transient Rb phosphorylation. Counteracting E2F-1 upregulation with antisense ODNs prevents neuronal loss. Taken together, these data demonstrate that Rb is a central player in regulating both caspase-dependent and -independent events leading to apoptosis.
Trinh
E
E
UMR 7519 CNRS-21, rue René Descartes, Strasbourg Cedex, 67 084, France.
Boutillier
A L
AL
Loeffler
J P
JP
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D015870:Gene Expression / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000166:cytology* / Q000201:enzymology; D009687:Nuclear Proteins; D010766:Phosphorylation; D011188:Potassium / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D020169:Caspases; D011188:Potassium