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Biology 207
Biology of Cancer
3/6/02
Lecture 10: Cell Signaling
Reading: Cooper Chap. 11
Reference: Lodish et al. Molecular Cell Biology. Fourth edition. Chap. 20.
Outline:
1. Proto-oncogenes and cell signaling pathways
a. growth factors
b. growth factor receptors
c. intracellular signaling
d. transcriptional activation
2. Cell death pathways
Lecture:
1. Pathways of cell signaling


Many oncogenes turn out to encode cell signaling molecules. When
proto-oncogenes are mutated, altered proteins are produced or the
proteins are overexpressed.
The normal cellular genes may encode growth factors, receptors, or
molecules involved in cell signaling.
a. Growth factors--Small molecules, often peptides (short proteins) that
stimulate cell growth and division.
Example:
PDGF=platelet derived growth factor.
 Oncogene name: sis.
 Under normal conditions stimulates cell growth.
 In cancer, growth factor is received by wrong type of cell or
too much is received.
b. Growth factor receptors--Proteins on the surface of cells that bind to
specific growth factors (ligands) and transmit signals to the cell.
Examples:



src, associated with sarcomas
erbB-2 (epidermal growth factor receptor) associated with
ovarian cancer
her-2/neu receptor, associated with aggressive breast
cancer
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 Receive signals from extracellular environment and convert this to
an intracellular signal.
 Under normal conditions, the receptor receives signals, passes
them on, then waits.
 In cancer, you may have too many receptors or receptors that
have a lower threshold for action.
 Mutations in the sequence encoding the receptor may leave it
effectively stuck in the ON position.
Many receptors such as src are kinases. They transfer phosphates to other
molecules such as proteins.
inactive protein +ATP  active protein-PO4 + ADP
c. Intracellular signaling.
Signal transduction--The processes a cell uses to transmit signals from the
outside to a location in the cell where action can be taken.

Signaling pathways involve interactions of various molecules (often
proteins) in an ordered sequence. Think of as a "bucket brigade".

Pathways can branch in different directions and different pathways can
culminate in the same molecule.
Example:
o ras (important in many cancers, including colon cancer and bladder
cancer)
o a guanine nucleotide binding protein
o acts as a molecular switch


Under normal conditions, the switch goes on and off
depending on the binding of GTP (active) or GDP (inactive).
In cancer, mutant ras contains a single amino acid
substitution that leaves ras in the active (GTP bound) state.
ALWAYS ON!
Ras receives information from receptor tyrosine kinases indirectly via adaptor
proteins.
In a signal transduction pathway, upstream signals pass on molecules to other
downstream molecules.
Growth factor + growth factor receptorinternal signal via tyrosine kinase of
receptor adaptor proteins ras  rafMEKMap kinaseactivated
transcription factor (SRF)
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Many of the proteins in signal transduction pathways have turned out to be
oncogenic when mutated or overexpressed, for example ras and raf.
Note: You need not learn an entire signal transduction pathway--whichever one
you learn will be out of date in months!
d. Transcription factors--Proteins that promote (or repress) the transcription of
particular genes.

Many of the cell signaling pathways end by activating transcription factors
that regulate particular genes involved in growth.

Transcription factors usually help RNA polymerase II to bind to the
promoter region of a gene and activate transcription.
Examples:
c-myc (associated with Burkitt's lymphoma)
fos
jun

Under normal conditions, these transcription factors only activate
transcription when they are phosphorylated or receive some other type of
signal.

In cancer, the transcription factors bind to DNA and activate genes without
having received a signal. They become stuck in the ON position.
2. Cell death pathways
Apoptosis=Programmed cell death--Precise sequence of intracellular events
that kill a cell when it is no longer needed by the body or it has been found to
contain a foreign (non-self) antigen.

A distinct category of oncogenes relate to the cell death pathway.
Example:
bcl-2 (associated with leukemias and lymphomas)

Under normal conditions, bcl-2 encodes a mitochondrial protein that
promotes cell survival.

In cancer, altered bcl-2 or too much bcl-2 results in not enough cell death.
Leads to proliferation of cells.

Lack of cell death is an important mechanism of cancer promotion among
cells of the immune system.
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