Chemistry of Life

Molecular genetics, biochemistry

cyclin-dependent kinases

Cyclin-dependent kinases are a subclass of serine/threonine protein kinases that can be either activated or deactivated depending upon the specific amino acid residue that is undergoing phosphorylated.

Cyclin-dependent kinases (CDKs) play a role in regulation of transcription and in mRNA processing, and in regulation of the cell cycle. Studies with yeast and embryonic cells suggest that mitosis is triggered by the periodic activation of cdc2 kinase (cdk1). This enzyme is a member of the Ser/Thr protein kinase family, and is a catalytic subunit of the highly conserved protein kinase complex known as M-phase promoting factor (MPF), which is essential for G1/S and G2/M phase transitions of eukaryotic cell cycle.

Mitotic cyclins form stable associations with cdk1 (cdc2), and function as regulatory subunits. The kinase activity of cdk1 is controlled by cyclin accumulation and destruction through the cell cycle. The phosphorylation and dephosphorylation of cdk1 play important regulatory roles in cell cycle control.

The small subunit of MPF is a protein kinase that can phosphorylate a variety of proteins when activated. Targets include:
a) Histone H1, which is bound to DNA and which, when phosphorylated may bring about chromosomal condensation.
b) The three major lamin proteins of the nuclear envelope, when hyperphosphorylated, lead to depolymerization of the nuclear membrane.
c) RNA polymerase in which phosphorylation may be responsible for inhibition of transcription during mitosis.
d) Regulatory subunit of cytoplasmic myosin, which, when phosphorylated, becomes inactive and is unable to function as an ATPase to drive the actin filaments involved in cell division. The inhibition of this myosin during the early stages of mitosis may prevent cell division until chromosomes separation is complete.

The small subunit of MPF has been remarkably conserved through evolution, and is virtually identical to a mitosis-inducing phosphoprotein, p34, synthesized by the yeast cdc2 gene.

The large subunit of MPF is cyclin B, a protein that combines with the cdc2 kinase of MPF to create the MPF complex. The cyclin B proteins in cleavage-stage cells exhibit periodic behavior, accumulating during S phase and decreasing during mitosis. Cyclins are often encoded by the mRNAs stored in the oocyte cytoplasm, and these cells cannot enter mitosis if the translation of cyclin-mRNA into proteins is selectively inhibited.

Cyclin B enables the cdc2 kinase subunit to become phosphorylated at residues threonine-14 (T-14), tyrosine-15 (Y-15), and threonine-161. Phosphorylation at T-161 is essential for MPF activity, but phosphorylations at T-14 and Y-15 inhibit MPF. So, when phosphorylated at all these positions, the kinase remains inactive but potentially functional. Levels of potentially functional MPF molecules (pre-MPF) accumulates during the late S period. Mitosis begins when the MPF kinase subunits are rapidly dephosphorylated at position Y-15 by cdc25 phosphatase.

MPF was the first member of a family of dimeric proteins with very similar structures to be discovered. Proteins of the family each contain a cyclin and a cyclin-dependent kinase, and at least seven cyclin-dependent kinases other than cdk1 are involved in mature vertebrate cells, while over a dozen cyclins have been identified. One of the most important of these enzymes is cyclin E/cdk2. Where MPF (cyclin B/cdk1) is essential for initiation of mitosis (M), cyclin E/cdk2 is critical for the cell’s ability to enter S phase, permitting DNA synthesis.

Harvard video of actin-myosin action.

. cell-cycle controlcellular adhesion moleculescellular signal transductioncentriolescyclin-dependent kinasescytokine receptors : DNA replicationGTPases : meiosismicrotubules : mitosis : mitotic spindle : molecular switchesreceptor proteinsnuclear membrane :



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. . . transcription begun 10/06/06