Caspase-3-mediated cleavage of Cdc6 induces nuclear localization of p49-truncated Cdc6 and apoptosis
- Authors
- Yim, H; Jin, YH; Park, BD; Choi, HJ; Lee, SK
- Issue Date
- Oct-2003
- Publisher
- AMER SOC CELL BIOLOGY
- Citation
- MOLECULAR BIOLOGY OF THE CELL, v.14, no.10, pp.4250 - 4259
- Indexed
- SCIE
SCOPUS
- Journal Title
- MOLECULAR BIOLOGY OF THE CELL
- Volume
- 14
- Number
- 10
- Start Page
- 4250
- End Page
- 4259
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/46659
- DOI
- 10.1091/mbc.E03-01-0029
- ISSN
- 1059-1524
- Abstract
- We show that Cdc6, an essential initiation factor for DNA replication, undergoes caspase-3-mediated cleavage in the early stages of apoptosis in HeLa cells and SK-HEP-1 cells induced by etoposide, paclitaxel, ginsenoside Rh2, or tumor necrosis factor-related apoptosis-inducing ligand. The cleavage occurs at the SEVD442/G motif and generates an N-terminal truncated Cdc6 fragment (p49-tCdc6) that lacks the carboxy-terminal nuclear export sequence. Cdc6 is known to be phosphorylated by cyclin A-cyclin dependent kinase 2 (Cdk2), an event that promotes its exit from the nucleus and probably blocks it from initiating inappropriate DNA replication. In contrast, p49-tCdc6 translocation to the cytoplasm is markedly reduced under the up-regulated conditions of Cdk2 activity, which is possibly due to the loss of nuclear export sequence. Thus, truncation of Cdc6 results in an increased nuclear retention of p49-tCdc6 that could act as a dominant negative inhibitor of DNA replication and its accumulation in the nucleus could promote apoptosis. Supporting this is that the ectopic expression of p49-tCdc6 not only promotes apoptosis of etoposide-induced HeLa cells but also induces apoptosis in untreated cells. Thus, the caspase-mediated cleavage of Cdc6 creates a truncated Cdc6 fragment that is retained in the nucleus and induces apoptosis.
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