Programmed cell death . See

Ca2+-activated endonucleases. These enzymes are involved with the normal process of apoptosis or "programmed cell death" (see below) and cleave DNA into fragments. This destruction of DNA results in cell death. Other enzymes involved in DNA fragmentation may also be activated by Ca2+. 

Programmed cell death. See Apoptosis Progress curve for enzyme-catalyzed reaction 455 Proinsulin 519 Projection formula Fisher 42 Newman 44... 

Precursor frequency, 198, 199f, 252 Prenatal diagnosis, 220-221 Probe, 252 Prochlorophytes, 206 Programmed cell death. See Apoptosis Propidium iodide, 64t, 67, 69t, 70, 124t, 253... 

The process involves a number of steps the interaction with or damage to DNA in a cell wiU lead to a tumour only if the cell divides and that damage is expressed. Only then does the uncontrolled division of the cell result in cancer. There are, however, protective mechanisms which can come into play. The DNA damage may be repaired, or if it is too extensive the cell may undergo a process called apoptosis or programmed cell death (see box above). This is a way in which the body removes single cells that have been damaged. Only if these processes are ineffective or overloaded will a tumour result. 

The nervous system is subject to a unique set of constraints during development. Many more neurons are generated during development than are required in the mature nervous system. Importantly, after their last mitotic division neurons are unable to re-enter the cell cycle and can no longer proliferate. As development proceeds there is a period during which as many as half of all neurons die, a process known as normal or programmed cell death that occurs by apoptosis of the cell (see Ch. 35). 

A signaling rheostat has been proposed where the relative level of SIP and ceramide determines cellular fate. This was based on the observation that ceramide, Fas and TNFa-mediated programmed cell death is suppressed by the addition of SIP (Cuvillier et al, 1996). The model assumes that ceramide is a physiological mediator of apoptosis although this is subject to controversy (Hofmann and Dixit, 1998 Kolesnick and Hannun, 1999). Indeed, sphingosine is also implicated as an apoptotic agent (see above). 

In addition to the endoplasmic reticulum, the mitochondria also function as an intracellular calcium reservoir. The mitochondria also play an important role in programmed cell death —apoptosis (see p. 396). 

The membrane-associated Akt kinase is now a substrate for protein kinase PDKl that phosphorylates a specific Thr and Ser residue of Akt kinase. The double phosphorylation converts Akt kinase to the active form. It is assumed that the Akt kinase now dissociates from the membrane and phosphorylates cytosolic substrates such as glycogen synthase kinase, 6-phosphofructo-2-kinase and ribosomal protein S6 kinase, p70 . According to this mechanism, Akt kinase regulates central metabolic pathways of the cell. Furthermore, it has a promoting influence on cell division and an inhibitory influence on programmed cell death, apoptosis. A role in apoptosis is suggested by the observation that a component of the apoptotic program. Bad protein (see Chapter 15) has been identified as a substrate of Akt kinase. 

Surprisingly, a growth inhibiting and pro-apoptotic function has been demonstrated for oncogenic Ras mutants. In primary cell cultures, activation of the Ras pathway is linked to an increase in the concentration of the tumor suppressor proteins p53 and pl9ARF (Serrano, 1997), which both promote programmed cell death, or apoptosis (see Chapter 15). This example shows that, according to the cellular context, the Ras protein can promote both cell death and cell survival via interactions with distinct effector proteins. 

Another route that a cell can take is the pathway of programmed cell death, or apoptosis (see Chapter 15). 

Apoptosis or programmed cell death is a program that brings about the death of the cell in a targeted maimer in the presence of DNA damage (see Chapter 15). Apoptosis is a protection against formation of tumor cells. If a cell is affected by DNA damage, apoptosis can help to initiate cell death before further mutations accumulate that would favor transition to the tumor state. The tumor suppressor protein p53 also plays an important role here. 

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