Back to Search
Start Over
Caspase-3-mediated cleavage of Cdc6 induces nuclear localization of p49-truncated Cdc6 and apoptosis.
- Source :
-
Molecular biology of the cell [Mol Biol Cell] 2003 Oct; Vol. 14 (10), pp. 4250-9. Date of Electronic Publication: 2003 Jun 27. - Publication Year :
- 2003
-
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.
- Subjects :
- Active Transport, Cell Nucleus physiology
Amino Acid Motifs
Annexin A5 metabolism
Apoptosis Regulatory Proteins
Caspase 3
Cell Membrane metabolism
Cyclin-Dependent Kinase 2
DNA Replication
Etoposide pharmacology
Flow Cytometry
Ginsenosides pharmacology
HeLa Cells
Humans
Membrane Glycoproteins pharmacology
Paclitaxel pharmacology
Phosphorylation
TNF-Related Apoptosis-Inducing Ligand
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha pharmacology
Apoptosis physiology
CDC2-CDC28 Kinases metabolism
Caspases metabolism
Cell Nucleus metabolism
Nuclear Localization Signals metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1059-1524
- Volume :
- 14
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecular biology of the cell
- Publication Type :
- Academic Journal
- Accession number :
- 14517333
- Full Text :
- https://doi.org/10.1091/mbc.e03-01-0029