9.6Signal Transduction for the Initiation of Cell Growth
Signal Transduction leading up to the Initiation of Cell Growth
Figure 9-7 shows a schematic diagram of the intracellular signal transduction that acts from the moment of a growth induction signal reaching a receptor on the plasma membrane to the initiation of cell growth. A transcription factor generated by a newly expressed early gene induces the expression of various genes. Among the genes expressed as a result, a group of protein kinases called cyclin-dependent kinases (CDKs) and a group of proteins required for their activation called cyclins are important. These two are synthesized, accumulated and form a complex; when activated, they phosphorylate other proteins (e.g., Rb) and consequently activate the transcription factors (e.g., E2F) of the genes necessary for DNA synthesis. This then activates gene-encoding enzymes that synthesize the DNA materials necessary in the S phase and DNA polymerase, thereby allowing the cell to enter the S phase.
Positive and Negative Regulation
The process of cell growth initiation also has both positive and negative regulation. Cyclins and CDKs are important as positive regulatory factors with a central role in the progression of cells through the cell cycle. On the other hand, a protein group called cyclin-dependent kinase inhibitors (CKIs) negatively regulates the cell cycle. These are synthesized by various signals that suppress cell growth in situations where, for example, cells adhere to each other or growth factors are absent, and suppress the activity of protein kinase by binding to CDKs (Fig. 9-7). CKIs degrade in environments where cells can grow. Another group of proteins that negatively regulate the progression of cells through the cell cycle is produced by genes collectively called tumor suppressor genes, which include Rb and p53 as shown in Figure. 9-7. In quiescent cells, these proteins suppress the genes necessary in the S phase, but the cells lose antiproliferative activity once Rb has been phosphorylated through the activation of CDKs by growth factors.
In this way, both positive and negative systems are often involved in many intracellular reactions.
Cyclins and CDKs - Involved in Every Stage of the Cell Cycle
As outlined in Figure. 9-7, the G1 cyclins and G1 CDKs act at the onset of the S phase. Cyclins and CDKs, each consisting of a group (family) of several similar proteins, also play an important role in helping cells progress through the cell cycle. As shown in Figure. 9-8, the G2 cyclins and G2 CDKs (cyclin B-Cdc2 complex) act at the onset of the M phase; once activated, they induce the breakdown of the nuclear envelope and the formation of chromosomes. There are several types of G1 cyclin and G1 CDK, including the cyclin D-CDK4/6 complex and the cyclin E-CDK2 complex, but these are not discussed here.
Cyclins are rapidly synthesized at certain stages of the cell cycle. Once their work is complete, they become ubiquitinated and rapidly degraded by protease elements called proteasomes. Degradation takes place not only because the cyclins are no longer needed but also because the process is often essential for cells to move on to the next stage of the cell cycle. Although CDKs, on the other hand, need to be synthesized for cells to exit the G0 phase and initiate growth, some types are degraded once they enter the cell cycle while others are not.
The overall picture of CDK activity regulation is very complex, and is governed by at least four mechanisms (Fig. 9-9). These are: synthesis and binding of cyclins; activation by phosphorylation; activity suppression by phosphorylation of the ATP binding site and activation by dephosphorylation; and activity suppression through the binding of CKIs. Although the overall picture is still not clearly understood, it is considered to be an intricate mechanism that causes DNA replication and cell division to progress relentlessly by performing molecular-level reactions (such as the synthesis and phosphorylation of proteins), using many types of factors.