Molecular Mechanisms for Regulating Mitotic Events

In the previous sections, we have seen that a regulated increase in MPF activity induces entry into mitosis. Presumably, the entry into mitosis is a consequence of the phosphorylation of specific proteins by the protein kinase activity of MPF. Although many of the critical substrates of MPF remain to be identified, we now know of examples that show how regulation by MPF phosphorylation mediates many of the early events of mitosis leading to metaphase: chromosome condensation, formation of the mitotic spindle, and disassembly of the nuclear envelope (see Figure 20-29).

Recall that a decrease in mitotic cyclins and the associated inactivation of MPF coincides with the later stages of mitosis (see Figure 21-9a). Just before this, in early anaphase, sister chromatids separate and move to opposite spindle poles. During telophase, microtubule dynamics return to interphase conditions, the chromosomes decondense, the nuclear envelope re-forms, the Golgi complex is remodeled, and cytokinesis occurs. Some of these processes are triggered by dephosphorylation; others, by protein degradation.

In this section, we discuss the molecular mechanisms and specific proteins associated with some of the events that characterize early and late mitosis. These mechanisms illustrate how cyclin-CDK complexes together with ubiquitin ligases control passage through the mitotic phase of the cell cycle.

Phosphorylation of Nuclear Lamins and Other Proteins Promotes Early Mitotic Events

The nuclear envelope is a double-membrane extension of the rough endoplasmic reticulum containing many nuclear pore

▲ FIGURE 21-16 The nuclear lamina and its depolymerization. (a) Electron micrograph of the nuclear lamina from a Xenopus oocyte. Note the regular meshlike network of lamin intermediate filaments. This structure lies adjacent to the inner nuclear membrane (see Figure 19-31). (b) Schematic diagrams of the structure of the nuclear lamina. Two orthogonal sets of 10-nm-diameter filaments built of lamins A, B, and C form the nuclear lamina (top). Individual lamin filaments are formed by end-to-end polymerization of lamin tetramers, which consist of two lamin dimers (middle). The red circles represent the globular N-terminal domains. Phosphorylation of specific serine residues near the ends of the coiled-coil rodlike central section of lamin dimers causes the tetramers to depolymerize (bottom). As a result, the nuclear lamina disintegrates. [Part (a) from U. Aebi et al., 1986, Nature 323:560; courtesy of U. Aebi. Part (b) adapted from A. Murray and T Hunt, 1993, The Cell Cycle: An Introduction, W. H. Freeman and Company.]

complexes (see Figure 5-19). The lipid bilayer of the inner nuclear membrane is supported by the nuclear lamina, a mesh-work of lamin filaments located adjacent to the inside face of the nuclear envelope (Figure 21-16a). The three nuclear lamins (A, B, and C) present in vertebrate cells belong to the class of cytoskeletal proteins, the intermediate filaments, that are critical in supporting cellular membranes (Chapter 19).

Lamins A and C, which are encoded by the same transcription unit and produced by alternative splicing of a single pre-mRNA, are identical except for a 133-residue region at the C-terminus of lamin A, which is absent in lamin C. Lamin B, encoded by a different transcription unit, is modified post-transcriptionally by the addition of a hydrophobic isoprenyl group near its carboxyl-terminus. This fatty acid becomes embedded in the inner nuclear membrane, thereby anchoring the nuclear lamina to the membrane (see Figure 5-15). All three nuclear lamins form dimers containing a rodlike a-helical coiled-coil central section and globular head and tail domains; polymerization of these dimers through head-to-head and tail-to-tail associations generates the intermediate filaments that compose the nuclear lamina (see Figure 19-33).

Early in mitosis, MPF phosphorylates specific serine residues in all three nuclear lamins, causing depolymeriza-tion of the lamin intermediate filaments (Figure 21-16b). The phosphorylated lamin A and C dimers are released into solution, whereas the phosphorylated lamin B dimers remain associated with the nuclear membrane via their isoprenyl anchor. Depolymerization of the nuclear lamins leads to disintegration of the nuclear lamina meshwork and contributes to disassembly of the nuclear envelope. The experiment summarized in Figure 21-17 shows that disassembly of the nuclear envelope, which normally occurs early in mitosis, depends on phosphorylation of lamin A.

(a) Interphase

(b) Prophase

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