Friday, March 26, 2010

Cell Cycle III: Entering and Exiting Mitosis (and the Events Between)

Today is the final part of the cell cycle that I will be writing, though more information about cell division will be posted eventually in the meiosis study notes.  I find that the pathways involved in mitosis are rather easy to understand, as everything fits together - it just takes some effort to realize how everything works with everything else. 
When the cell is ready to begin anaphase, the sister chromatids must be aligned at the metaphase plate, and the proper Cdk/cyclin must remain activated (Cdc2/cyclin B).  When anaphase is to begin, APC/C (anaphase promoting complex / cyclosome) activates via phosphorylation from Cdk/cyclin and association with a cofactor.  APC/C acts as a ubiquitin ligase and is involved in poly-ubiquitinating proteins to target them for degradation.  When phosphorylated APC/C binds Cdc20, it targets securin for degradation.  Securin typically holds a protein called separase.  When securin releases separase, the protein cleaves cohesion complexes and separates sister chromatids.  This prompts the cell to enter anaphase when the sister chromatids migrate away from each other.  This process is regulated by Bub and Mad2, which act to inhibit the action of APC/CCdc20.  When a checkpoint is activated by a sister chromatid not being bound to a kinetochore MT, for example, it actively signals to Bub, which activates Mad2 to activate Mad2*.  Mad2* is involved in inhibiting the APC/CCdc20 complex.  The end result is that the sister chromatids do not separate. 

During anaphase, the microtubules are undergoing a number of changes.  Initially in anaphase (Anaphase A), the kinetochore microtubules, bound to the kinetochores of the sister chromatids, begin to shorten, pulling the chromatids apart.  During anaphase B, the astral microtubules remain in place, maintaining the spindle pole in place.  The polar microtubules begin to push on each other by elongating, which pushes the spindle poles apart and promotes separation of the nuclei.  When the spindles have moved apart and the chromatids have separated, APC/C targets Ase1p for degradation, which leads to breakdown of the spindle. 

When cohesion is cleaved by separase (see above), Cdc14 phosphatase is released from the nucleolus.  This event is the signal to end mitosis by inducing expression expression of Sic1, which acts to deactivate MPF.  Cdc14 dephosphorylates and activates Cdh1, which complexes with APC/C to target MPF for degradation.

With MPF degraded proteolytically, the nuclear envelope is free to reform.  Constitutive phosphatases dephosphorylate the lamins and nuclear pore complexes.  This results in the formation of karyomeres, which are small vesicles (with nuclear pores in them) that form around the sister chromatids.  The karyomeres then fuse to reform the nuclear envelope. 

In addition to the nuclear lamins and pore complexes, myosin light chain is also dephosphorylated when MPF is degraded.  This results in the activation of the protein and the initiation of cytokinesis when the contractile ring begins to form.

A quick summary…

Phase of the Cell Cycle
The cell is preparing to duplicate; centrosomes appear outside the nucleus
Early Prophase
Spindle poles form and sister chromatids condense
Late Prophase
Sister chromatids are condensed and begin to be attached by kinetochore MTs
Sister chromatids align at the metaphase plate
The cell begins to divide the sister chromatids by releasing them to each pole
The nuclear envelope reforms and the cells begin to structurally split

The cell cycle isn’t so scary, but it certainly is complex, and not all of the components and regulatory mechanisms have been discussed here (or discovered in the literature either!).  Nonetheless, it is crucial to understand the basics of the cell cycle because it is so intimately related to nearly all biological processes.

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