Cdc2

APC/C

APC/C active

APC/C

CM^C

Separin-securin Active separin

All kinetochores attached; 'wait anaphase' signal extinguished

Separin-securin Active separin

Metaphase

(aligned chromosomes)

Cohesin cleavage

Anaphase (separation of sister chromatids)

Figure 3.1.1.B, Sister chromatid separation. (a) In prometaphase, cells contain condensed chromosomes that actively establish bipolar attachments to the mitotic spindle. Unattached chromosomes generate a signal that delays progress to anaphase until all sister chromatids are attached to the spindle apparatus. This signal is transduced by a relay of spindle checkpoint proteins that include CENPE and the MAD/BUB proteins. This ultimately results in inhibition of the anaphase promoting complex/cyclosome (APC/C), which is associated with the mitotic cofactor CDC20. (b) Following attachment of the last kinetochore to the mitotic spindle, the "wait anaphase" signal is extinguished. This allows APC/C and CDC20 to become active, resulting in the Ubiquitin-dependent degradation of Securin and liberation of active Separin. This protease catalyzes the cleavage of Cohesin complexes that bridge the aligned sister chromatids. The newly separated sister chromatids can then migrate to the poles along the spindle axis during anaphase. PLK = Polo-Like Kinases, Ub = Ubiquitin. [Reproduced from Jallepalli and Lengauer 2001. With permission from Macmillan.]

Metaphase

(aligned chromosomes)

Cohesin cleavage

Anaphase (separation of sister chromatids)

Figure 3.1.1.B, Sister chromatid separation. (a) In prometaphase, cells contain condensed chromosomes that actively establish bipolar attachments to the mitotic spindle. Unattached chromosomes generate a signal that delays progress to anaphase until all sister chromatids are attached to the spindle apparatus. This signal is transduced by a relay of spindle checkpoint proteins that include CENPE and the MAD/BUB proteins. This ultimately results in inhibition of the anaphase promoting complex/cyclosome (APC/C), which is associated with the mitotic cofactor CDC20. (b) Following attachment of the last kinetochore to the mitotic spindle, the "wait anaphase" signal is extinguished. This allows APC/C and CDC20 to become active, resulting in the Ubiquitin-dependent degradation of Securin and liberation of active Separin. This protease catalyzes the cleavage of Cohesin complexes that bridge the aligned sister chromatids. The newly separated sister chromatids can then migrate to the poles along the spindle axis during anaphase. PLK = Polo-Like Kinases, Ub = Ubiquitin. [Reproduced from Jallepalli and Lengauer 2001. With permission from Macmillan.]

- In the prometaphase stage, the nuclear envelope breaks down, so there is no longer a recognizable nucleus. The mitotic spindle fibers elongate from the centrioles and attach to the kinetochores, protein bundles located on the chromosomes. The growth of microtubules from the centrosomes is mediated by polymerization that is controlled by GTP caps, which can exist if the rate of GTP hydrolysis lags slightly behind that of Tubulin polymerization. Ends without a GTP cap have high Tubulin off rates and shrink, whereas ends with a GTP cap grow [Mitchison and Kirschner 1984a,b]. Tubulin is the protein subunit of the microtubules [Weisenberg et al. 1968].

- Tension applied by the spindle fibers in metaphase aligns all chromosomes in one plane at the center of the cell.

- In anaphase, spindle fibers shorten, the kineto-chores separate, and the chromatids (daughter chromosomes) are pulled apart and begin moving to the cell poles. Anaphase begins when the APC destroys Securin. This releases the inhibition of the protease Separin and allows the breakdown of Cohesins, which hold sister chromatids together. Anaphase is triggered by the proteolysis of the Cohesin subunit SCC-1 by a Separase.

- The daughter chromosomes arrive at the poles in telophase. The spindle fibers that have pulled them apart disappear.

- In cytokinesis, the spindle fibers begin to break down. A contractile ring cleaves the cell into two daughter cells. This process involves components of the central spindle, RHO-A and its regulators or effectors, nonmuscle Myosin II, Actin and regulators of filament assembly, and factors required for the fusion of membranes. The central spindle consists of the microtubulin-associated proteins Polycomb Repressive Complex 1 (PRC1) and KIF4, the centralspindlin complex MGC/RAC-GAP (CYK-4) and MKLP1, the RHO-Guanine Nucleotide Exchange Factor (GEF) ECT2, and the Aurora Kinase complex with Aurora B/Incep/Survivin/Dasra. The RHO-A GTPase module plays a central role in contractile ring assembly, with its critical GEF being ECT2 and CYK-4 possibly acting as its GAP. RHO-A-GTP activates pathways that lead to Actin polymerization and Myosin II activation. The micro-tubules then reorganize into a new cytoskeleton for the return to interphase. The exit from the cytokinetic phase of the cell cycle depends on

Ubiquitin-mediated proteolysis of various M phase-selective proteins. After the cells complete mitosis, the fall in CDK/Cyclin levels leads to the dephosphorylation of RB by phosphatases. As a consequence, hypo-phosphorylated RB protein is available to inhibit E2F activity during early G1 of the next cycle.

Consistent with their critical role in facilitating cell divisions, the components of the cell cycle are frequently deregulated in cancer. This may arise through activating mutations or through overexpression of their genes.

• Cyclin Dj/CDK4 kinase activity is elevated in various cancers, including head and neck cancer, hepatocellular carcinoma, and colorectal carcinoma, either through the overproduction of cyclin D1 or through mutations in cdk4, which make Cyclin D1 insensitive to the inhibitory effects of

P16INK4a

• Overexpression of Cyclin D is associated with about 50% of breast cancers.

• The overexpression of Cyclin D3 and Cyclin A occur early in pancreatic intraepithelial neoplasia and reach close to 100% prevalence in pancreatic cancer. A common substitution polymorphism A870G in the ccndl gene, which encodes Cyclin D1, occurs in the conserved splice donor region of exon 4. It results in an altered mRNA transcript that encodes a protein with prolonged half-life and is associated with colorectal cancer.

• PLK-1 is overexpressed in tumors and may be a prognostic indicator in non-small cell lung cancer, squamous cell carcinoma of the head and neck, melanoma, oropharyngeal cancer, ovarian, and endometrial carcinomata.

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