Early Embryonic Development
Maternal effect gene products set the stage by
controlling the expression of the first embryonic
genes.
1. Transcription factors
2. Receptors
3. Regulatory proteins
Maternal effect gene products form a gradient of
concentration across the embryo.
Zygotic Genes
Zygotic genes are the first genes expressed by the
embryo in response to signals from the maternal
effect genes.
The first of these genes are broadly classed into two
categories, segmentation genes and selector genes.
Zygotic Genes
Segmentation genes
1.
2.
Divide the embryo into segments
Define the number, size and polarity of each
segment.
Zygotic Genes
Selector genes specify the identity or fate of each
segment.
Segment Formation
Segmentation is controlled by three classes of genes:
1. Gap proteins
2. Pair-rule genes
3. Segment polarity genes
These gene products act in a coordinated fashion to
divide the embryo into segments, then create an
orientation within the segments.
Development
Once the segments have been formed, selector genes
are activated and specify the developmental fate of
cells within the segment.
Selector genes determine the structures that will
ultimately form.
Genetics and Cancer
Normal cell function and cell lifespan is closely
regulated by careful regulation of the timing of
cell division.
Cancer is, at its core, unregulated tissue growth:
1) Uncontrolled cell division
2) Metastasis, or spread, of cancer cells away from
their original site to other locations in the body.
Mutations and Cancer
Mutations that influence the development and
progression of cancer can be small or large:
1. Small changes, such as a single base mutation or
frameshift mutation that results in an abnormal
protein.
2. Large changes such as chromosomal losses, gains
or rearrangements, or integration of viral
genomes into chromosomes.
Mutations and Cancer
Mutations will always arise at some spontaneous rate
because of inherent imperfections in the DNA
replication process.
Carcinogens are environmental substances that
impair the replication process at some level such
that mutations are introduced at a rate above
baseline and promote the formation of cancer.
Known Mutagens and Carcinogens
Ionizing radiation
Viruses
Environmental chemicals
Typically, more than one mutational event must
occur.
Cancer Susceptibility Genes
Cancer is known to run in families, though usually
there is no clear-cut pattern of inheritance.
Individuals may inherit a mutant alelle that
predisposes them to cancer (increases risk of
developing cancer) by influencing the age of onset
and severity of cancer.
Cell Cycle
The phases of the cell cycle are the G1, S, G2
(interphase) and M phases.
Some cell types continuously move through the cell
cycle (skin, GI tract lining), dividing at regular
intervals.
Other cell types move through the cell cycle only
intermittently.
Some cell types withdraw from the cell cycle and
enter a permanently non-dividing state called G0.
Cell Cycle
Progression from one phase to the next is tightly
controlled.
Cell-cycle checkpoints are the places in the cell cycle
in which progression are regulated. The major
checkpoints are at the transitions from
1) G1 to S
2) G2 to M
3) M (transition into anaphase)
Cell-Cycle Regulation
Any mutation that interferes with regulation of the
cell cycle is a candidate carcinogen.
De-regulation of the cell-cycle disrupts the ability of
a cell to control its division and increases the
probability of unrestricted cell growth.
Control of Cell Division
Control of cell division is both negative and positive.
1. Inhibition of cell division (tumor suppressor
genes)
2. Promotion of cell division (protooncogenes)
Tumor Suppressor Genes
Under normal circumstances, tumor suppressor
genes halt progression through the cell cycle. For
cell division to occur, these gene products must be
absent or inactivated.
If tumor suppressor genes become permanently
inactivated or deleted, control of cell division is
lost and the cell enters uncontrolled proliferation.
Usually, both alleles must be mutant for tumor
suppressor activity to be lost.. (One normal copy is
enough to suppress cell division) Recessive
Major Tumor Suppressors
Retinoblastoma gene (Rb): Controls the G1 to S
transition. Although it is always expressed such
that the protein is normally present, cells can make
the G1/S transition only when Rb is inactivated by
phosphorylation.
Wilms tumor gene (WT): Encodes a transcription
factor that controls cell division, although the
precise function is unknown.
Major Tumor Suppressor Genes
p53: A transcription factor involved in cell cycle
arrest, DNA repair and induction of apoptosis
(programmed cell death). At least 20 genes are
known to be regulated by p53, and as much as 50%
of all cancers are thought to be associated with
malfunctions in p53.
BRCA1/BRCA2: Breast cancer susceptibility genes,
thought to be involved in DNA repair mechanisms.
Protooncogenes
When these genes are activated, they promote cell
division.
For cell division to be “turned off,” these genes must
be absent or inactivated.
If protooncogenes are permanently “turned on,” the
cells enter into uncontrolled proliferation.
Major Protooncogenes
Protooncogenes are the normal form of oncogenes.
Oncogenes are the mutant alleles that cause cancer
by promoting uncontrolled cell growth.
Typically, only one mutant allele is sufficient to deregulate cell growth. (Dominant)
Many oncogenes are identified with viruses.
Major Oncogenes
Src: A membrane protein originally identified as the
transforming principle of Rous sarcoma virus
(RSV)
Ras: A signal transduction protein that transmits
signals from the external cell environment and
promotes cell division.
Metastasis
Metastasis is invasion of cancer cells into other parts
of the body, where they divide and form secondary
tumors.
Metastasis is often what ultimately causes death from
cancer.
Cancer cells escape the primary tissue by entering
the blood or lymphatic system.
Metastasis
Tumor cells with high metastatic capacity produce
large amounts of enzymes called
metalloproteinases, which digest the
extracellular framework and allow the tumor cells
to penetrate and migrate.
Normal cells inhibit migration by producing
TIMP, or Tissue Inhibitor of Metalloproteinases.
Metastasis occurs when there is not enough TIMP
to suppress metalloproteinase activity.