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CELL CYCLE - Coggle Diagram

- - - - are the cell cycle engines and we are able to control the events of the cell cycle by regulating CDKs activity.
      - they are protein complexes formed by specific kinases (Cdk, that more or less remain constant during the cycle) that are the enzymatic subunits that will then be associated with cyclins ( that will change during the cycle)
- - - - Cell Dimension is checked
        if it not big enough it will not pass in the S phase
    - - cells have specific receptors on the cell surface able to detect signals → molecules secreted by other cells
        
        pheromones or mating factors
        
        they activate the downstream kinase that phosphorylates other kinases and so on amplifying the signal from the surface and regulating the CDK engine
      - in higher eukaryotes
        
        a specific receptor that detects mitogens
        
        the mitogens activates the receptor that molecularly transmits the signal to other downstream kinases ➜ MAPK family
        
        the mitogen-induced signaling pathway, as in yeast, controls the cell cycle in G1/S phase
- - - - cdc mutants are able to grow at permissive temperature and stop at restrictive temperature in a specific point since a specific factor is not expressed .
        then when shifted to the permissive T again the cell division resumes
        
        they collected several mutations that stop at different stages of the cell cycle.
        They were also combined
        
        ⤳ cdc15 and cdc16.
        they both block in the mitotic stage, but
        cdc15 blocks after the nuclei are divided
        cdc16 blocks at metaphase with short spindle and the 2 copies of the chr are not
        yet segregated
      - cdc28→ it is able to block the cell in 2 different stages (G1/S and M)
        
        decided to clone the cdc28 allele and sequence the gene
        
        self complementation with a library and and isolated the cdc28 gene in a plasmid
        
        small gene encoding for a protein kinase, later called cdk1 that was very similar to the S.Pombe cdc2
        
        Sequence alignment also with the human ones.
        ➜ the aa identiy is very high anf they are characterized by the T-loop domain
        
        fundamental loop for the regulation of 50% of the protein kinases
        → it regulates the access into the catalytic site of the substrate
  - - - REGULATION
        
        regulated by different mechanisms:
        a. association of different cyclins in different cell cycle stages
        b. regulatory events that control directly the post-translational modifications of cdk (kinases and phosphatases)
        c. association with specific inhibitors
        
        INHIBITORS AND ACTIVATORS OF CDKs
        
        ❖ cyclins > activators
        ❖ CKI (CDK Kinase Inhibitor)
        → the inhibitor associates with a specific box of the complex and this interaction is controlled by phosphorylation of critical residues, so it can allow strong association of the inhibitor or the release of this association
        
        CDK-Cyclin complexed throughout the cell cycle
        
        • CDK6 and CDK4 - cyclin D → involved in early stages (G1 and S)
        • CDK2 - cyclin A → involved in the S phase
        • CDK1-cyclin A → involved in the late stages (G2,M)
        ➜ cyclin and CKIs are regulated though Ub-dependent degradation
        
        PROTEIN DEGRADATION
        
        SCF
        
        1 more item...
        
        APC
        
        2 more items...
        
        fundamental regulatory mechanism to control cell division and compared to phosphorylation degradation is an irreversible mechanism
        
        how is the active state of CDK regulated?
        
        → cdk associate with cyclin forming the active complex
        → the T-loop has to be phosphorylated (it extrudes outside so that the active site is open
      - CDKs for cancer therapy
        
        inhibition of CDK1 as a potential therapy for tumors overexpressing MYC
        
        PLK
        
        very conserved family of protein kinases.
        
        N-terminal kinase domain (with the T-loop)
        
        C-Terminal domain (where there is the PBD)
        
        mutations in the PKLs can lead to tumorigenesis