Page 60 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 2 Tumor Biology and Metastasis 39

DNA Damage
e.g., ionizing radiation p21
GADD45 Cell cycle
VetBooks.ir Signaling through ATM Cyclin G arrest

Bax Apoptosis
IGFBP3

transcriptional mdm2
activation
Stabilization
of p53

mdm2 p53 complex
26S proteosome
degradation ubiquitination
• Fig. 2.3 The mediators of apoptosis. A wide variety of signals can initiate an apoptotic response, includ-
ing Fas ligand (CD95 or FasL) and its interaction with the Fas receptor, tumor necrosis factor (TNF) and
its receptor interaction, and certain oncogenes. The Fas and TNF receptors are members of the death
receptor family. These are transmembrane proteins with cysteine-rich extracellular domains and intracel-
lular regions that share a common structure termed the death domain. The proapoptotic ligands for these
receptors are homotrimeric peptides that are either soluble or expressed at the surface of the adjacent
cell. Ligand-induced receptor clustering promotes the binding of a soluble cytosolic adapter protein called
Fas-associated death domain (FADD), which itself contains a death domain, in addition to a caspase
binding site, to the clustered death domains of the receptors. This leads to activation of caspase 8 and
downstream activation of effector caspases for apoptosis.

Cell Death death domain and a caspase binding site, to the clustered death
domains of the receptors. This leads to activation of caspase 8
If DNA damage is extensive and the cell cannot repair itself, and downstream activation of effector caspases for apoptosis
then the cell may be triggered to die by apoptosis. In contrast (Fig. 2.5).
to necrosis, apoptosis is a distinct type of cell death most often If cells are damaged and unable to repair DNA, p53 expression
characterized as the “programmed” self-destruction of cells that can upregulate p21 and cause cell cycle arrest or can aid in direct-
occurs in disease states and also as part of normal physiologic ing the cell into programmed death or apoptosis through upregu-
cell turnover. Whereas necrosis is characterized by swelling of lation and expression of Bax (a proapoptotic Bcl-2 family protein)
the cell and lysis, apoptosis is marked by cellular and nuclear and also through priming of caspases. In this, the expression of
shrinkage followed by fragmentation and subsequent phago- p53 can also downregulate expression of the Bcl2 gene itself (a
22
cytosis. These morphologic features of apoptosis result from prosurvival, negative regulator of apoptosis).
a number of apoptosis effectors (i.e., caspases) and regulators
(particularly the Bcl-2 protein family). The molecular mecha- Key Points
26
nisms involved in apoptosis are shown in Fig. 2.4. Apopto-
sis provides a controlled mechanism for eliminating cells that • The cell cycle ensures a regulated process so that each cell can
are irreversibly damaged; it involves an adenosine triphosphate complete DNA replication before cell division occurs.
(ATP)–dependent activation of cellular pathways, which move • The cell responds to growth and environmental signals through
calcium from the endoplasmic reticulum to the cytoplasm and the cell cycle.
activation of endonucleases. As noted previously, some of these • Cancer is a common disease; however, the formation of cancer
pathways are mediated through caspases. However, a wide vari- is actually a rare event, because of tightly regulated DNA repair
ety of signals can initiate an apoptotic response, including Fas mechanisms in the cell.
ligand (CD95 or FasL) and its interaction with the Fas recep- • Cellular responses to DNA damage are regulated through
tor, tumor necrosis factor (TNF) and its receptor interaction, ATM and ATR, which act as “sensory kinases.”
and certain oncogenes. The Fas and TNF receptors are mem- • The cellular response to DNA damage is either to inhibit cell
bers of the death receptor family. These transmembrane pro- cycle progression (allowing repair) or to facilitate entry into
teins with cysteine-rich extracellular domains and intracellular an apoptosis pathway. Failure to do this has the potential to
regions share a common structure termed the “death domain.” promote the malignant phenotype.
The proapoptotic ligands for these receptors are homotrimeric • Components of the cell cycle that have a stimulatory effect
peptides that are either soluble or expressed at the surface of include the cyclins and the CDKs. The negative influences
the adjacent cell. Ligand-induced receptor clustering pro- come from a series of checkpoints that respond to external
motes the binding of a soluble cytosolic adapter protein called stimuli. These include tumor suppressor genes, such as p53 and
Fas-associated death domain (FADD), which itself contains a Rb, and also genes involved in DNA repair.