Cell Cycle Arrest via Controls

Cell Cycle Arrest via Controls

While the proliferation of cells through growth and division is important for the function of the organism, there are occasions in which the cycle needs to be halted in order to allow for proper control of what genetic material is being passed on to the next generation. Such methods of control can be via the activation of various factors which stop the cell cycle from continuing during various stages of interphase.

One type of control is via the activation of ATM and ATR after DNA damage. Activation of ATM (double strand breaks) and ATR (single stranded or unreplicated DNA) causes the phosphorylation of Chk2 and Chk1 respectively. These phosphorylated and activated factors then phosphorylate Cdc25, a protein phosphatase which normally dephosphorylates the inhibitory sites on a cyclin dependent kinase (Cdk). Without ATM and ATR, Cdc25’s dephosphorylation of the two inhibitory sites (more specifically Thr-14 and Tyr-15) on Cdk causes the inhibition of the inhibitory sites and ultimately the activation of the Cdk/Cyclin complex. If the complex is activated, mitosis can occur. However, ATM and ATR phosphorylates this Cdc25 protein, which inhibits it and thus prevents it from removing the phosphates from Cdk. This ultimately causes cell cycle arrest for it prevents the cell from entering mitosis. If Cdk1’s inhibitory sites are prevented from dephosphorylation (stays phosphorylated and active), the cell cycle is arrested in the G2 phase. By contrast, though in a similar manner, prevention of dephosphorylation of the Thr-14 and Tyr-15 inhibitory sites on Cdk2 causes cellular arrest in G1 or S phase.

Note: the initial phosphorylation of the inhibitory sites is accomplished by Wee1. There is also an activation site on the Cdk which is phosphorylated by CAK (usually around the Tyr-160 positon).

Another method is through the activation of a tumor suppressor called p53, which leads to production of p21. Again, ATM’s activation causes the phosphorylation and activation of Chk2. Phosphorylation of Chk2 will cause the phosphorylation/stabilization of the p53 tumor suppressor (also a transcription factor). Activated p53 transcription factors will bind to DNA and initiate the production of p21. Once p21 is produced, it will eventually bind to the Cdk2/Cyclin E and inhibit the cell’s growth at the G1 stage.

Finally, I believe it also is important to note that, during G1 phase, Cdk4,6/Cyclin D (complex necessary to get cell past restriction point in G1) will cause the formation of Cyclin E. This is done through a transcription factor called E2F. Normally, E2F is bound by a retinoblastoma protein (Rb), which prevents the cell from proliferation. Phosphorylation of Rb will cause it to release E2F, allowing the latter to bind to DNA and allow for transcription of Cyclin E. Creation of Cyclin E, along with the eventual formation of the Cdk2/Cyclin E complex, will induce the cell to enter S phase. However, again, the Rb tumor suppressor normally prevents such occurrence by the inhibition of Cyclin E through the inhibition of E2F.

#cell #mitosis #growth #cellbiology #biology #cancer #DNA #genetics #cellcycle #phosphorylation