Transcript Lecture Slides 5

Apoptosis is a form of programmed cell death
Apoptosis
Necrosis
Apoptosis is responsible for the formation of digits
in the developing mouse paw.
Chapter 18
Apoptotic cells are
biochemically recognizable.
Apoptosis is a form of programmed cell death
* Programmed cell death removes unwanted cells during
development.
* Apoptotic cells are biochemically recognizable.
* In apoptotic cells, phosphatidylserine flips from the inner leaflet to
the outer and serves as an “eat me” signal to phagocytic cells.
* Apoptosis depends upon an intracellular proteolytic cascade that is
mediated by caspases.
* The two best understood signaling pathways that can activate a
caspase cascade are known as the extrinsic pathway and the
intrinsic pathway.
* The intrinsic pathway is regulated by a set of pro- and antiapoptotic proteins that are related to Bcl2.
* Either excessive or insufficient apoptosis can contribute to disease.
Apoptosis depends upon an intracellular proteolytic
cascade that is mediated by caspases.
Caspase: They have a cysteine in their active site and cleave substrates at
specific aspartic acid residues.
Figure 18-5a
Apoptosis depends upon an intracellular proteolytic
cascade that is mediated by caspases.
Initiator
Executioner
Targets
Figure 18-5b
The intrinsic pathway of apoptosis
Figure 18-8
Release of cytochrome c from mitochondria during apoptosis
Figure 18-7
The intrinsic pathway of apoptosis
Figure 18-8
Pro-apoptotic Bcl2 proteins stimulate the release of
mitochondrial intermembrane proteins
Figure 18-9, 10
The interplay between the pro- and anti-apoptotic Bcl2
proteins determines the activity of the intrinsic pathway
Figure 18-11a Molecular Biology of the Cell (© Garland Science 2008)
The interplay between the pro- and anti-apoptotic Bcl2
proteins determines the activity of the intrinsic pathway
Figure 18-11b Molecular Biology of the Cell (© Garland Science 2008)
Decreased apoptosis can contribute to tumorigenesis
Figure 20-14
CANCER
* Cancers are monoclonal in origin and multiple mutations are
generally required for their progression.
* Tumor progression involves successive rounds of random inherited
change followed by natural selection.
* A small population of cancer stem cells can be responsible for the
maintenance of tumors.
* Tumor metastasis is a complex, multi-step process.
* Cancer-critical genes fall into two major classes: oncogenes and
tumor suppressor genes.
* Cancer progression typically involves changes in both of these
types of genes
* The Rb and p53 proteins are two of the most important tumor
suppressor gene products for human cancer.
Cancers are generally monoclonal in origin
Evidence from X-inactivation mosaics that demonstrates the monoclonal origin of cancers.
Figure 20-6 Molecular Biology of the Cell (© Garland Science 2008)
Cancer incidence increases with age
Figure 20-7 Molecular Biology of the Cell (© Garland Science 2008)
Tumor progression involves
successive rounds of random
inherited change followed by
natural selection
Figure 20-11 Molecular Biology of the Cell (© Garland Science 2008)
Oncogene collaboration in mice: Further evidence for the
requirement for multiple mutations during tumor formation
Figure 20-36
Cancers
may arise
from cancer
stem cells
Figure 20-16 Molecular Biology of the Cell (© Garland Science 2008)
Tumor metastasis is a complex multi-step process
Fig 20-17
An assay used to detect the presence of an oncogene:
the loss of contact inhibition in culture
Figure 20-29 Molecular Biology of the Cell (© Garland Science 2008)
Some of the major pathway relevant to cancer in human cells
Figure 20-37 Molecular Biology of the Cell (© Garland Science 2008)
Distinct pathways may
mediate the disregulation
of cell-cycle progression
and the disregulation of
cell growth in cancer
cells
Figure 20-39a Molecular Biology of the Cell (© Garland Science 2008)
Dominant & recessive mutations that contribute to cancer
Figure 20-27
The types of events that can make a proto-oncogene overactive and convert
it into an oncogene.
Figure 20-33 Molecular Biology of the Cell (© Garland Science 2008)
Chronic Myelogenous Leukemia (CML) & the
Philadelphia chromosome
Figure 20-5
(Hyperactive Abl)
Figure 20-51
Targeted therapy: the success of Gleevec
Specifically targeting the Abl enzyme
Binds to Abl in active site &
“locks” the enzyme into an
inactive state
Figure 20-52 Molecular Biology of the Cell (© Garland Science 2008)
Targeted therapy: the success of Gleevec
Specifically targeting the Abl enzyme
Figure 20-52c Molecular Biology of the Cell (© Garland Science 2008)
Multidrug Therapy: Combating Resistance
Figure 20-53 Molecular Biology of the Cell (© Garland Science 2008)
The genetic mechanisms that cause retinoblastoma
Figure 20-30 Molecular Biology of the Cell (© Garland Science 2008)
Figure 20-31
Examples of the ways in which the one good copy of a tumor suppressor locus
might be lost through change in DNA sequence,
The loss of tumor suppression
gene function can involve both
genetic and epigenetic changes
Figure 20-32
A simplified view of
the Rb pathway
Figure 20-38a
The Rb protein inhibits entry into the cell cycle
Figure 20-38b,c Molecular Biology of the Cell (© Garland Science 2008)
Mechanisms controlling
cell-cycle entry and S-phase
initiation in animal cells
A central role for the
Rb protein
Figure 17-62 Molecular Biology of the Cell (© Garland Science 2008)
Figure 17-62 (part 1 of 3) Molecular Biology of the Cell (© Garland Science 2008)
Figure 17-62 (part 2 of 3) Molecular Biology of the Cell (© Garland Science 2008)
The inactivation of the Rb protein is
needed for the entry into S-phase
Figure 17-62 (part 3 of 3) Molecular Biology of the Cell (© Garland Science 2008)