Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Mol Biol Cell. 2011 Apr 15;22(8):1191-206. doi: 10.1091/mbc.E10-07-0599. Epub 2011 Feb 16.

Mitotic progression becomes irreversible in prometaphase and collapses when Wee1 and Cdc25 are inhibited.

Author information

  • 1Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. tpo@stowers.org

Abstract

Mitosis requires precise coordination of multiple global reorganizations of the nucleus and cytoplasm. Cyclin-dependent kinase 1 (Cdk1) is the primary upstream kinase that directs mitotic progression by phosphorylation of a large number of substrate proteins. Cdk1 activation reaches the peak level due to positive feedback mechanisms. By inhibiting Cdk chemically, we showed that, in prometaphase, when Cdk1 substrates approach the peak of their phosphorylation, cells become capable of proper M-to-G1 transition. We interfered with the molecular components of the Cdk1-activating feedback system through use of chemical inhibitors of Wee1 and Myt1 kinases and Cdc25 phosphatases. Inhibition of Wee1 and Myt1 at the end of the S phase led to rapid Cdk1 activation and morphologically normal mitotic entry, even in the absence of G2. Dampening Cdc25 phosphatases simultaneously with Wee1 and Myt1 inhibition prevented Cdk1/cyclin B kinase activation and full substrate phosphorylation and induced a mitotic "collapse," a terminal state characterized by the dephosphorylation of mitotic substrates without cyclin B proteolysis. This was blocked by the PP1/PP2A phosphatase inhibitor, okadaic acid. These findings suggest that the positive feedback in Cdk activation serves to overcome the activity of Cdk-opposing phosphatases and thus sustains forward progression in mitosis.

PMID:
21325631
[PubMed - indexed for MEDLINE]
PMCID:
PMC3078080
Free PMC Article

Images from this publication.See all images (7)Free text

FIGURE 1:
FIGURE 2:
FIGURE 3:
FIGURE 4:
FIGURE 5:
FIGURE 6:
FIGURE 7:

Publication Types, MeSH Terms, Substances, Grant Support

Publication Types

MeSH Terms

Substances

Grant Support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk