Malfunction of the restriction checkpoint at the G1 phase may also result in malignant transformation of cells. Malignant cells lose contact inhibition, a normal process in which cells inhibit their division when they contact other cells. Malignant cells in culture continue to divide and may grow on top of one another rather then discontinuing growth when the plate is fully covered in a monolayer of cells. The malfunction of the restriction checkpoint may be facilitated by the viral proteins of several cancer-causing viruses, such as the T-antigen of simian virus (SV40) that binds to pRb. This binding alters the configuration of the pRb–T-antigen complex and renders the restriction checkpoint inoperable, thus facilitating the cell’s progression from the G1 to S phase of the cell cycle. This mechanism of carcinogenesis occurs in mesothelioma (cancer of the lining epithelium of the pleural cavities in the thorax), osteosarcoma (a type of bone cancer), and ependymoma (a type of childhood brain tumor).
The reserve stem cell population may become activated and reenter the cell cycle.
Cells identified as reserve stem cells may be thought of as GO cells that may be induced to reenter the cell cycle in response to injury of cells within the tissues of the body. Activation of these cells may occur in normal wound healing and in repopulation of the seminiferous epithelium after intense acute exposure of the testis to X-irradiation or during regeneration of an organ, such as the liver, after removal of a major portion. If damage is too severe, even the reserve stem cells die, and there is no potential for regeneration.
Regulation of the Cell Cycle
Passage through the cell cycle is driven by proteins that are cyclically synthesized and degraded during each cycle.
A number of cytoplasmic protein complexes regulate and control the cell cycle. Some of these proteins function as
TABLE Functional Summary of Cyclin–Cdk Complexes Used in Regulating the Human Cell Cycle3.1 Associated Cyclin-Cyclin Type Dependent Protein Kinase Targeted Phase of Cell Cycle Targeted Effector Proteins Cyclin D Cdk4/6 G1 phase progression Tumor-suppressing protein p53, retinoblastoma susceptibility protein (pRb) Cyclin E Cdk2 S phase entry ATMA or ATRB protein kinases, tumor-suppressing protein p53 Cyclin A Cdk2 S phase progression Replication protein A, DNA polymerase, minichromosome maintenance (Mcm) protein Cyclin A Cdk1 S phase through G2 phase Cdc25 phosphatase, cyclin B and M phase entry Cyclin E Cdk1 M phase progression Chromatin-associated proteins, histone H1, nuclear lamins, myosin regulatory proteins, centrosomal proteins, transcription factors c-fos/jun, c-myb, oct-1, SWI5; p60src protein kinases, casein kinase II, c-mos protein kinases A Ataxia–telangiectasia mutated protein kinase B ATM—and Rad3—related kinase biochemical oscillators, whose synthesis and degradation are coordinated with specific phases of the cycle. Cellular and molecular events induced during the increase and decrease of different protein levels are the basis of the cell-cycle “engine.” Other proteins actively monitor the quality of the molecular processes at the different checkpoints distributed throughout the cycle (described above). The protein complexes at the checkpoints may drive the cell into and out of the cell cycle, stimulating growth and division when conditions are favorable and, conversely, stopping or reducing the rate of cell division when conditions are not favorable.
A two-protein complex consisting of cyclin and a cyclindependent kinase (Cdk) helps power the cells through the checkpoints of cell-cycle division.