TY - JOUR
T1 - Chromatin modification of Apaf-1 restricts the apoptotic pathway in mature neurons
AU - Wright, Kevin M.
AU - Smith, Michelle I.
AU - Farrag, Lila
AU - Deshmukh, Mohanish
PY - 2007/12/3
Y1 - 2007/12/3
N2 - Although apoptosis has been extensively studied in developing neurons, the dynamic changes in this pathway after neuronal maturation remain largely unexplored. We show that as neurons mature, cytochrome c-mediated apoptosis progresses from inhibitor of apoptosis protein-dependent to -independent regulation because of a complete loss of Apaf-1 expression. However, after DNA damage, mature neurons resynthesize Apaf-1 through the cell cycle-related E2F1 pathway and restore their apoptotic potential. Surprisingly, we find that E2F1 is sufficient to induce Apaf-1 expression in developing but not mature neurons. Rather, Apaf-1 up-regulation in mature neurons requires both chromatin derepression and E2F1 transcriptional activity. This differential capacity of E2F1 to induce Apaf-1 transcription is because of the association of the Apaf-1 promoter with active chromatin in developing neurons and repressed chromatin in mature neurons. These data specifically illustrate how the apoptotic pathway in mature neurons becomes increasingly restricted by a novel mechanism involving the regulation of chromatin structure.
AB - Although apoptosis has been extensively studied in developing neurons, the dynamic changes in this pathway after neuronal maturation remain largely unexplored. We show that as neurons mature, cytochrome c-mediated apoptosis progresses from inhibitor of apoptosis protein-dependent to -independent regulation because of a complete loss of Apaf-1 expression. However, after DNA damage, mature neurons resynthesize Apaf-1 through the cell cycle-related E2F1 pathway and restore their apoptotic potential. Surprisingly, we find that E2F1 is sufficient to induce Apaf-1 expression in developing but not mature neurons. Rather, Apaf-1 up-regulation in mature neurons requires both chromatin derepression and E2F1 transcriptional activity. This differential capacity of E2F1 to induce Apaf-1 transcription is because of the association of the Apaf-1 promoter with active chromatin in developing neurons and repressed chromatin in mature neurons. These data specifically illustrate how the apoptotic pathway in mature neurons becomes increasingly restricted by a novel mechanism involving the regulation of chromatin structure.
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U2 - 10.1083/jcb.200708086
DO - 10.1083/jcb.200708086
M3 - Article
C2 - 18056406
AN - SCOPUS:36849041089
SN - 0021-9525
VL - 179
SP - 825
EP - 832
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 5
ER -