Embedded in the cell cycle are surveillance mechanisms primed to sense DNA or chromosomal damage. These quality-control checkpoints ensure that cells with genetic imperfections do not complete replication. Thus, the G1-S checkpoint monitors the integrity of DNA before irreversibly committing cellular resources to DNA replication. Later in the cell cycle, the G2-M check point ensures that there has been accurate DNA replication before the cell actually divides. When cells do detect DNA irregularities, checkpoint activation delays cell-cycle progression and triggers DNA repair mechanisms. If the genetic derangement is too severe to be repaired, the cells either undergo apoptosis or enter a nonreplicative state called senescence— primarily through p53-dependent mechanisms (see later).
Enforcing the cell-cycle checkpoints is the job of CDK inhibitors (CDKIs); they accomplish this by modulating CDK-cyclin complex activity. There are several different CDKIs:
One family of CDKIs—composed of three proteins called p21 (CDKN1A), p27 (CDKN1B), and p57 (CDKN1C)— broadly inhibits multiple CDKs
Another family of CDKIs has selective effects on cyclin CDK4 and cyclin CDK6; these proteins are called p15 (CDKN2B), p16 (CDKN2A), p18 (CDKN2C), and p19 (CDKN2D)
Defective CDKI checkpoint proteins allow cells with damaged DNA to divide, resulting in mutated daughter cells at risk for malignant transformation
An equally important aspect of cell growth and division is the biosynthesis of other cellular components needed to make two daughter cells, such as membranes and organelles. Thus when growth factor receptor signaling stimulates cell-cycle progression, it also activates events that promote changes in cellular metabolism that support growth. Chief among these is the Warburg effect, mentioned earlier, marked by increased cellular uptake of glucose and glutamine, increased glycolysis, and (counterintuitively) decreased oxidative phosphorylation. These changes are major elements of cancer-cell growth and are discussed in greater detail in Chapter 6.
Not all stem cells are created equal. During development, totipotent stem cells can give rise to all types of http://ebooksmedicine.net
Fig. 1.18 Roleofcyclins,CDKs,andCDKinhibitorsinregulatingthecellcycle.Shaded arrows representthephasesofthecellcycleduringwhichspecificcyclin-CDKcomplexesareactive.Asillustrated,cyclinD-CDK4,cyclinD-CDK6,andcyclinE-CDK2regulatetheG1-to-StransitionbyphosphorylatingtheRbprotein(pRb).CyclinA-CDK2andcyclinA-CDK1areactiveintheSphase.CyclinB-CDK1isessentialfortheG2-to-Mtransition.TwofamiliesofCDKinhibitorscanblockactivityofCDKsandprogressionthroughthecellcycle.Theso-called“INK4inhibitors,”composedofp16,p15,p18,andp19,actoncyclinD-CDK4andcyclinD-CDK6.Theotherfamilyofthreeinhibitors,p21,p27,andp57,caninhibitallCDKs.
differentiated tissues; in the mature organism, adult stem cells in various tissues only have the capacity to replace damaged cells and maintain cell populations within the tissues where they reside. There also are populations of stem cells between these extremes with varying capacities to differentiate into multiple cell lineages. Thus, depending on the source and stage of development, there may be limits on the cell types that a stem cell population can generate.
In normal tissues (without neoplasia, degeneration, or healing), there is a homeostatic equilibrium between the replication, self-renewal, and differentiation of stem cells and the death of the mature, fully differentiated cells (