Role of Cyclins and CDKs


Role of Cyclins and CDKs

  • Two key classes of regulatory molecules, cyclins and cyclin-dependent kinases (CDKs), determine a cell’s progress through the cell cycle.  
  • Many of the genes encoding cyclins and CDKs are conserved among all eukaryotes, but in general more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. 
  • Many of the relevant genes were first identified by studying yeast, especially Saccharomyces cerevisiae; genetic nomenclature in yeast dubs many of these genes cdc (for “cell division cycle”) followed by an identifying number, e.g., cdc25.
  • Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated heterodimer; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. 
  • When activated by a bound cyclin, CDKs perform a common biochemical reaction called phosphorylation that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. 
  • Different cyclin-CDK combinations determine the downstream proteins targeted. CDKs are constitutively expressed in cells whereas cyclins are synthesized at specific stages of the cell cycle, in response to various molecular signals.
  • Cyclin-dependent kinases (CDKs) are typical serine/threonine kinases that display the 11 subdomains shared by all kinases. 
  • Among the 19,099 predicted genes, there are 14 CDKs and 34 cyclins; nine CDKs and 11 cyclins have been identified in man, referred to as CDK1-CDK9. 
  • This also allows the activating phosphorylation on Thr160 (by CDK7/cyclin H/MAT1). 
  • The second conformational change induced by cyclin binding is found within the ATP-binding site where a reorientation of the amino acid side chains induces the alignment of the triphosphate of ATP necessary for phosphate transfer. 
  • The strong sequence homology between the catalytic domains of different CDKs suggests that their tridimensional structures will be similar. 
  • Progression through the G1, S, G2 and M phases of the cell division cycle is directly controlled by CDKs. 
  • In early-mid G1, extracellular signals modulate the activation of CDK4 and CDK6 associated with D-type cyclins.
  • These complexes phosphorylate and inactivate the retinoblastoma protein pRb, resulting in the release of the E2F and DP1 transcription factors which control the expression of genes required for the G1/S transition and S phase progression. 
  • The CDK2/cyclin E complex, which is responsible for the G1/S transition, also regulates centrosome duplication. 
  • During S phase, CDK2/cyclin A phosphorylates different substrates allowing DNA replication and the inactivation of G1 transcription factors. 
  • Around the S/G2 transition, CDK1 associates with cyclin A. 
  • Later, CDK1/cyclin B appears and triggers the G2/M transition by phosphorylating a large set of substrates. 
  • Phosphorylation of the anaphase promoting complex (APC) by CDK1/cyclin B is required for transition to anaphase and completion of mitosis

General mechanism of cyclin-CDK interaction

  • Upon receiving a pro-mitotic extracellular signal, G1 cyclin-CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication. 
  • The G1 cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination. 
  • Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome. 
  • Active S cyclin-CDK complexes phosphorylate proteins that make up the pre-replication complexes assembled during G1 phase on DNA replication origins. 
  • The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. 
  • This ensures that every portion of the cell’s genome will be replicated once and only once. 
  • The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. 
  • However, for reasons related to gene copy number effects, possession of extra copies of certain genes would also prove deleterious to the daughter cells.
  • Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of mitosis by stimulating downstream proteins involved in chromosome condensation and mitotic spindle assembly. 
  • A critical complex activated during this process is a ubiquitin ligase known as the anaphase-promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetophore. 
  • APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.

Specific action of cyclin-CDK complexes

  • Cyclin D is the first cyclin produced in the cell cycle, in response to extracellular signals (eg. growth factors). 
  • Cyclin D binds to existing CDK4, forming the active cyclin D-CDK4 complex. 
  • Cyclin D-CDK4 complex in turn phosphorylates the retinoblastoma susceptibility protein (RB). 
  • The hyperphosphorylated RB dissociates from the E2F/DP1/RB complex (which was bound to the E2F responsive genes, effectively “blocking” them from transcription), activating E2F. 
  • Activation of E2F results in transcription of various genes like cyclin E, cyclin A, DNA polymerase, thymidine kinase, etc. 
  • Cyclin E thus produced binds to CDK2, forming the cyclin E-CDK2 complex, which pushes the cell from G1 to S phase (G1/S transition). 
  • Cyclin A along with CDK2 forms the cyclin A-CDK2 complex, which initiates the G2/M transition. 
  • Cyclin B-CDK1 complex activation causes breakdown of nuclear envelope and initiation of prophase, and subsequently, its deactivation causes the cell to exit mitosis.
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