Transcription factor (p53)


Figure 10.1 • Cyclins and the cell cycle.

cells such as nerve cells never divide. If the cell is to undergo division, it will progress to the S phase where DNA is replicated. This is followed by the G2 phase, during which additional protein synthesis occurs including the formation of the microtubules. The M phase, which is further subdivided into prophase, metaphase, anaphase, and telophase, follows in which the DNA is segregated and cell division occurs. During the entire cycle, movement from one phase to the next is driven by proteins known as cyclins and their associated cyclin-dependent kinases (CDKs). There are several subtypes of cyclins with their CDKs, the concentrations of which change or cycle as the cell moves from G1 through M phase, and this concentration change is associated with moving the cell into the next phase. The D-type cyclins paired with CDK4/6 are in high concentration during the G1 phase, and their formation is under the control of external growth factors. Subsequent to this, the D-type cyclins help drive the formation of cyclin E with its CDK2, which drives the cell from the G1 to the S phase. This is followed by formation of A- and B-type cyclins with their CDKs, which push the cell into G2 and subsequently into M, respectively.

The progression through the cell cycle is a highly regulated process, and the cell is constantly monitoring itself to make sure that the necessary enzymes are present and the genome is intact. If problems are encountered, the cell may be slowed from progressing or undergo programmed cell death also known as apoptosis. Regulation of the cell through the cell cycle is the function of the tumor suppressor proteins such as retinoblastoma protein (Rb), p21Cip1, and p53.2 Especially important in this regard is p53, sometimes referred to as the guardian of the cell, it functions as a transcription factor and may activate genes, the products of which are involved in the repair of DNA. When damage becomes too severe to be repaired, p53 may direct the cell to die. One of the best examples of this is seen during overexposure to the sun. The UV damage that the skin has suffered is detected by p53 and the cells undergo apoptosis with the resulting peeling away of the dead skin.3 Activation of p53 may occur in response to various stresses that cause damage to the genome, but it has been found that in many cancer cells, p53 and other tumor suppressor genes are not functioning. Although a normal cell would undergo apopto-sis in this situation, the cancerous cells continue to survive and may mutate more readily because the system of genetic checks and balances is no longer in place.

The process of apoptosis can occur by both an intrinsic and extrinsic pathway (Fig. 10.2). The intrinsic pathway begins when cytochrome c is released from the mitochondria via channels present in the mitochondrial membrane. The state of this channel is controlled by several different proteins such that opening is stimulated by the proapoptotic p53 products Bad, Bax, and Bid and closure is stimulated by the antiapoptotic Bcl-2 and Bcl-XL proteins. Opening of the channel releases cytochrome c into the cytoplasm where it combines with apoptotic protease activating factor-1 (apaf-1) molecules to form a wheel-like structure of seven spokes known as the apoptosome. This then binds and activates caspase-9, which activates additional caspase enzymes in a cascade fashion. The caspase enzymes cleave numerous proteins within the cell, leading to profound morphological changes and cell death.

The extrinsic pathway is activated when ligands of the tumor necrosis factor family of proteins (TNF-a, FasL, TRAIL) interact with the so-called death receptors (FAS, DR3-5, TNFR1) present on the cell surface. This interaction serves to covert procaspase to active caspase-8/10, which is capable of activating the executioner caspases directly, and in this process, the proapoptotic Bid is activated by caspase-8, which opens the mitochondrial channel allowing for the release of cytochrome c. This then functions as it had in the intrinsic pathway to form the apoptosome.

The ability of drugs to kill cancer cells is generally believed to be because of their ability to induce the process of apoptosis. In high-dose therapy, cell death may occur by necrosis but this is also toxic to the patient. In a general sense, the antineoplastics target DNA or the process of DNA replication and stimulate apoptosis but the exact mechanisms by which this stimulation occurs are not known with certainty. The effectiveness of the agents is reduced in cells where apo-ptosis fails to occur properly, and this is a property of many cancer cells. Normal cells with fully functioning apoptotic

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Conquering Fear In The 21th Century

Conquering Fear In The 21th Century

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