Anaphase-promoting Complex/Cyclosome-dependent Proteolysis of Human Cyclin A Starts at the Beginning of Mitosis and Is Not Subject to the Spindle Assembly Checkpoint

doi:10.1083/jcb.153.1.137

Published online 2 April 2001. doi:10.1083/jcb.153.1.137

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© The Rockefeller University Press, 0021-9525/2001/4/137/ $5.00
The Journal of Cell Biology, Volume 153, Number 1, April 2, 2001 137-148

Original Article

Anaphase-promoting Complex/Cyclosome–dependent Proteolysis of Human Cyclin A Starts at the Beginning of Mitosis and Is Not Subject to the Spindle Assembly Checkpoint

Stephan Geley^a, Edgar Kramer^b, Christian Gieffers^b, Julian Gannon^a, Jan-Michael Peters^b, and Tim Hunt^a
^a Imperial Cancer Research Fund Clare Hall Laboratories, South Mimms, Herts EN6 3LD, United Kingdom
^b Institute for Molecular Pathology, A-1030 Vienna, Austria

Correspondence to: Tim Hunt, ICRF Clare Hall Labs, South Mimms, Potters Bar, Herts EN6 3LD, UK. Tel:44-20-7269-3981 Fax:44-20-7269-3804 E-mail:tim.hunt{at}icrf.icnet.uk.

Cyclin A is a stable protein in S and G2 phases, but is destabilizedwhen cells enter mitosis and is almost completely degraded beforethe metaphase to anaphase transition. Microinjection of antibodiesagainst subunits of the anaphase-promoting complex/cyclosome(APC/C) or against human Cdc20 (fizzy) arrested cells at metaphaseand stabilized both cyclins A and B1. Cyclin A was efficientlypolyubiquitylated by Cdc20 or Cdh1-activated APC/C in vitro,but in contrast to cyclin B1, the proteolysis of cyclin A wasnot delayed by the spindle assembly checkpoint. The degradationof cyclin B1 was accelerated by inhibition of the spindle assemblycheckpoint. These data suggest that the APC/C is activated ascells enter mitosis and immediately targets cyclin A for degradation,whereas the spindle assembly checkpoint delays the degradationof cyclin B1 until the metaphase to anaphase transition. The"destruction box" (D-box) of cyclin A is 10–20 residueslonger than that of cyclin B. Overexpression of wild-type cyclinA delayed the metaphase to anaphase transition, whereas expressionof cyclin A mutants lacking a D-box arrested cells in anaphase.

Key Words: cyclin A, ubiquitin, APC/C, spindle assembly checkpoint, mitosis

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