Abstract
Apoptosis in human monocytic THP.1 tumour cells, induced by diverse stimuli, was accompanied by proteolytic cleavage of the adenomatous polyposis coli gene product (APC) and by sequential cleavage of the retinoblastoma susceptibility gene product (Rb). Cleavage of poly(ADP-ribose) polymerase (PARP), APC and the initial cleavage of Rb at the carboxy terminal region all occurred at a similar time, early in the apoptotic process. Subsequently, Rb underwent a secondary cleavage to 43 kDa and 30 kDa protein fragments. Two caspase inhibitors, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD.FMK) and acetyl-Tyr-Val-Ala-Asp chloromethyl ketone (YVAD.CMK), had markedly different effects on the induction of apoptosis. Z-VAD.FMK inhibited the primary and secondary cleavage of Rb, cleavage of APC and PARP, and apoptosis assessed by flow cytometry. In marked contrast, YVAD.CMK inhibited cleavage of APC and the secondary cleavage of Rb to the 43 kDa and 30 kDa protein fragments but did not inhibit the primary carboxy terminal cleavage of Rb, PARP proteolysis or apoptosis assessed by flow cytometry. These results suggest that different caspases are responsible for the cleavage of different substrates at different stages during the apoptotic process and that a caspase may either cleave APC directly or may be involved in the pathway leading to APC proteolysis. This is the first report suggesting that a cytoplasmic tumour suppressor gene (APC) may be cleaved by a caspase during apoptosis.
Similar content being viewed by others
Article PDF
Author information
Authors and Affiliations
Additional information
Edited by M. Piacentini
Rights and permissions
About this article
Cite this article
Browne, S., MacFarlane, M., Cohen, G. et al. The adenomatous polyposis coli protein and retinoblastoma protein are cleaved early in apoptosis and are potential substrates for caspases. Cell Death Differ 5, 206–213 (1998). https://doi.org/10.1038/sj.cdd.4400331
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.cdd.4400331
Keywords
This article is cited by
-
Uev1A promotes breast cancer cell survival and chemoresistance through the AKT-FOXO1-BIM pathway
Cancer Cell International (2019)
-
Mechanisms Regulating Microtubule Binding, DNA Replication, and Apoptosis are Controlled by the Intestinal Tumor Suppressor APC
Current Colorectal Cancer Reports (2011)
-
Caspase cleavage of the APC tumor suppressor and release of an amino-terminal domain is required for the transcription-independent function of APC in apoptosis
Oncogene (2007)
-
Drosophila caspase transduces Shaggy/GSK-3β kinase activity in neural precursor development
The EMBO Journal (2005)
-
Epithelial proliferation induces novel changes in APC expression
Oncogene (2005)