Cyclins and cyclin-dependent kinases (cdks)

 Cyclins

Cyclical changes in their concentrations that occur over a series of cell divisions.
Highly specific to cdk.

Concentration of cyclin protein is dependent on the transcription of its gene and

by subsequent regulated protein degradation.

Regulatory subunits of their cdks.

 Cyclin dependent kinase (cdk)

Cyclin binding induces a conformational change in the catalytic subunit of the

cdk revealing its active site.

The cyclin–cdk complexes: Phosphorylating target proteins.

Targets: Transcriptional regulators, cytoskeletal proteins, nuclear pore and

envelope proteins, and histones. Specific examples include condensins,
nuclear lamins, GM130 of the Golgi apparatus, the famous transcriptional
regulator, retinoblastoma protein (RB or pRB),and transcription factors E2F
and Smad 3.
 Mechanisms of cdk regulation
 Association with cyclins,

 Association with cdk inhibitors (p16 and

p21),

 Addition of phosphate groups that activate

cdk activity.

 Addition of phosphate groups that inhibit

cdk activity

Activation: transcriptional regulation of the

cyclin genes and by protein degradation.

Degradation of cyclin proteins is carried out

by the proteasome, a complex of proteases.

Ubiquitin ligase: Adds ubiquitin to lysine of

cyclins for degradation by the proteasome.
Cell cycle checkpoints
Mechanisms of RB protein
SPINDLE ASSEMBLY CHECKPOINT
 The Spindle-assembly Checkpoint
In nondisjunction, chromosomes segregate in anaphase prior to attachment of the
kinetochores of all sister chromatids to mitotic spindle fibers. This results in unequal
segregation of chromosomes to daughter cells.
 Microtubules as anticancer drug targets

MTA treatment Apoptosis

Improper
spindle EB1 Mitotic block
Multipolar spindles
alignment
Perturbed EB1 localization

Suppressio
n of
microtubul
e dynamics Monopolar spindles
Mad 2 BubR1
Accumulation of SAC proteins

Rai A, Gupta T K, Kini S, Kunwar A, Surolia A and Panda D 2013 CXI-benzo-84 reversibly binds to tubulin at colchicine site
and induces apoptosis in cancer cells Biochem Pharmacol 86 378-91.