Sensory Transduction in Vision, Olfaction, and Gustation:- CDKs Regulate Cell Division by Phosphorylating Critical Proteins
We have examined how cells maintain close control of CDK activity, but how does the activity of CDK control the cell cycle? The list of target proteins that CDKs are known to act upon continues to grow, and much remains to be learned. But we can see a general pattern behind CDK regulation by inspecting the effect of CDKs on the structures of laminin and myosin and on the activity of retinoblastoma protein. The structure of the nuclear envelope is maintained in part by highly organized meshworks of intermediate filaments composed of the protein laminin. Breakdown of the nuclear envelope before segregation of the sister chromatids in mitosis is partly due to the phosphorylation of laminin by a CDK, which causes laminin filaments to depolymerize.
A second kinase target is the ATP-driven actin myosin contractile machinery that pinches a dividing cell into two equal parts during cytokinesis. After the division, CDK phosphorylates a small regulatory subunit of myosin, causing dissociation of myosin from actin fil aments and inactivating the contractile machinery. Sub sequent dephosphorylation allows reassembly of the contractile apparatus for the next round of cytokinesis. A third and very important CDK substrate is the retinoblastoma protein, pRb; when DNA damage is detected, this protein participates in a mechanism that arrests cell division in G1 (Fig. 12–46). Named for the retinal tumor cell line in which it was discovered, pRb functions in most, perhaps all, cell types to regulate cell division in response to a variety of stimuli. Unphosphorylated pRb binds the transcription factor E2F; while bound to pRb, E2F cannot promote transcription of a group of genes necessary for DNA synthesis (the genes for DNA polymerase , ribonucleotide reductase, and other proteins; Chapter 25). In this state, the cell cycle cannot proceed from the G1 to the S phase, the step that commits a cell to mitosis and cell division. The pRb E2F blocking mechanism is relieved when pRb is phosphorylated by cyclin E–CDK2, which occurs in response to a signal for cell division to proceed. When the protein kinases ATM and ATR detect dam age to DNA, such as a single-strand break, they activate p53 to serve as a transcription factor that stimulates the synthesis of the protein p21 (Fig. 12–46). This protein inhibits the protein kinase activity of cyclin E–CDK2. In the presence of p21, pRb remains unphosphorylated and bound to E2F, blocking the activity of this transcription factor, and the cell cycle is arrested in G1. This gives the cell time to repair its DNA before entering the S phase, thereby avoiding the potentially disastrous trans fer of a defective genome to one or both daughter cells.
FIGURE 12–46 Regulation of passage from G1 to S by phosphorylation of pRb. When the retinoblastoma protein, pRb, is phosphorylated, it cannot bind and inactivate EF2, a transcription factor that pro motes synthesis of enzymes essential to DNA synthesis. If the regulatory protein p53 is activated by ATM and ATR, protein kinases that detect damaged DNA, it stimulates the synthesis of p21, which can bind to and inhibit cyclin E–CDK2 and thus prevent phosphorylation of pRb. Unphosphorylated pRb binds and inactivates E2F, blocking passage from G1 to S until the DNA has been repaired.
