Question

What do you think would happen in mutant cells with the following defects and why? a. Cannot degrade M phase cyclins b. Inactivated CDK c. Have a mutated p53

Answer 1

a. Cannot degrade M phase cyclins:

M cdk cyclin complex is synthesized during S phase and G2 phase, but it is activated only after the end of DNA replication. The activated MCdk complex induces the chromosome condensation, breakdown of nuclear membrane and mitotic spindle formation. MCdk complex also activates the Anaphase Promoting Complex (APC) which in turn promotes the Anaphase changes in the cell division

If M phase cyclins are not degraded the decondensation of chromosomes and reorganization of nuclear membrane does not occur, the cells further undergo uncontrolled cell division which may lead to proliferation of the cell mass

b. Inactivated CDK: Cyclin Dependent kinases (Cdk) complexes play a vital role in G1 check point, G2 check point and M checkpoints. G1 check point, a critical checkpoint mediated G1-Cdk complex allows the transition into of G1 phase to S phase and M Cdk complex act as G2 checkpoint after which the cell enters the division phase

Inactivated Cdk leads to entry of Faulty fragments of DNA (which may have occured during S phase), faulty proteins (which may have produced during G2 phase) to enter into M phase that leads to faulty daughter cells in the cell division without regulating them  

c. Have a mutated p53: p53 gene is associated with cell cycle regulation by producing a transcriptional activator. Transcriptional activator regulates the expression of other genes that control the cell cycle. P53 produces Cyclin kinase inhibitor (CKI) that inactivates the Cdk cyclin complex by which cell is arrested at G1 check point to allow damaged DNA to repair.

Mutated p53 results in failure of repair to the damaged DNA. P53 gene codes for p53 protein that suppress the protooncogenes. When p53 genes are mutated or deleted, it results in the failure of dectivation of oncogenes which induces cancer formation

EXTRA INFORMATION:

DETAILED EXPLANATION OF CELL CYCLE AND ITS REGULATION

The cell cycle consists of division phase and interphase which lasts for 20-24 hrs. Based on the synthetic activities occuring, the Cell cycle is divided into G1, S and G2 phases.

G1 phase is an active propagation phase which begins after mitosis. Cytoplasmic elements like ribosomes, membrane bound organelles, substrates and enzyme necessary for DNA replication are synthesized during this phase.

S phase is the one in which the DNA content of the cell is doubled

G2 Phase is characterised by increased nuclear volume. Proteins required for spindle formation are produced during this phase

M phase is the division phase in which the mitiotic division takes place.

Cell cycle regulation: Cell cycle is regulated by Cyclins and kinases. Cyclins are regulatory subunits which are further subdivided into G1 cyclin, S cyclin and M cyclin. Kinases are the phosphorylating enzymes and always associated with cyclins, hence called as Cyclin dependent Kinases. The levels of Cyclins during the cell cycle are not constant where as the kinases remain uniform.

Kinases add phosphate group to proteins that control the process of cell cycle. Cdk Cycilin complexes are G-Cdk, S-Cdk, M-Cdk.

When cells are stimulated to divide, G1 Cdk-cyclin complex first appears which prepares the cell for S phase, activates factors required for DNA replication. It also blocks the inhibior of S-Cdk cyclin complex. S-Cdk complex phosphorylates the proteins necessary for DNA replication in S phase. M-Cdk cyclin complex which is synthesized during S phase and G2 phase is activated at the end of DNA replication. Upon activation it induces the chromosome condensation, breakdown of nuclear membrane and mitotic spindle formation. It also activates the Anaphase promoting Complex(APC) which is responsible for anaphase changes during cell division. Decrease in MCdk complex helps in the decondensation of chromosomes and reorganization of nuclear membrane which helps in completion of cell division.

Checkpoints:

The different checkpoints of cell cycle are G1 checkpoint, G2 Checkpoint, and M or final checkpoint. The critical point in the cell cycle is G1 check point which allows the transition of G1 into S phase. The concentration and acitivity of G1-Cdk complex act as G1 check point. Once the transition occurs, the remaining cycle can be complete.

A second transition occurs at G2 checkpoint in which concentration and activity of MCdk acts as checkpoint. Through G2 checkpoint cell cycle enter cell division. The final check point is during division itself which regulates the formation of spindle fibres and their attachment to the centromere. This is not controlled by Cdk complex but it is a enzymatic process

The genes thta regulate the gene cycle in mammals is p52 or Tumor suppressor gene.