Transcript Cell Cycle Control & Oncogenesis - Fall 2007, Campbell & Del Gaizo

Endocrinology & Cancer
Endocrinology 317/319
Department of Biology
University of Massachusetts Boston
Kenneth L. Campbell
&
Victoria Del Gaizo Moore
Overview of main points to be covered:
Cell Cycle Control
What can go wrong
Stages of Cancer Development
Specific Examples of Cancers
Oncogenesis - Chemical Signaling and Cancer
Basic Concepts
Tumor
Benign (self contained)
Malignant (migratory, prone to seeding tumors at other sites)
Hypertrophy - hypertrophic cells; hyperplastic tissue
Neoplasia - new, often irregular, growth or tissue
Proto-oncogenes = Normal gene precursors of oncogenes
I
V
Mutational Agents
I
V
Oncogenes = Gene associated with abnormal cell growth
Oncogene Product = Expressed protein coded by an oncogene
Mutagens
Radiation, Chemical - tend to be small changes, insertions, deletions, or base changes
Chromosome Rearrangements (in meiosis) - can be large changes, deletions, inversions
Viral Rearrangement - viruses can become lysogenic & excise & carry genes or foreign
promoter DNA to subsequent cellular hosts where these insert into non-homologous sites
& are expressed in a non-regulated or inappropriately regulated fashion, often leading to
oncogenesis via disruption of the normal events of the cell cycle or cell cycle regulatory
points.
Mitotic Cell Cycle & Its Controls
Normal Cell Cycle & Controls
Rb
p53, p21
route to apoptosis
role of DNA repair
Normal Stages of Mitosis shown
by time.
Cells receive cues from their
environment (surrounding cells
and tissues) that help direct it
to undergo division
Each cell must monitor DNA
replication to make sure that
synthesis is correct, fixing any
mistakes along the way.
During DNA replication the two strands are copied in opposite
directions using different methods. Topoisomerase is also involved
and makes cuts in one or both strands that must be ligated to
maintain sequence integrity. Thus, there are opportunities for
sequence mismatches or replication mistakes even during mitosis.
The anti-parallel, helical, frequently coiled and supercoiled nature of
DNA within cells presents topological problems during replication that
can result in mistakes that must be monitored by the cell cycle
machinery.
Rb protein: the first major checkpoint
pRB- retinoblastoma protein
named so because in retinoblastoma cancer both alleles of
the gene are mutated so no protein is produced
pRb prevents the cell from dividing or progressing through
the cell cycle when DNA is damaged.
Control occurs at S (DNA synthesis phase) because
pRb binds and inhibits transcription factors of the E2F family
When pRb is ineffective at this role, mutated cells
can continue to divide and may become cancerous.
pRB regulation depends on phosphorylation
pRb can actively inhibit cell cycle progression when it is
dephosphorylated
Therefore phosphorylation inactivates its function.
At the end of mitosis (M phase) pRB depends on a phosphatase
to dephosphyorylate it, allowing it to bind to E2F
pRb the Master Controller:
The First Checkpoint
Robert A. Weinberg, How Cancer Arises, Scientific American 275(3):62-70,
September 1996.
Phosphorylation of pRb
by cyclin/cyclin-kinase
complexes allows
release of pRb-bound
transcription factors
such as E2F. Now free,
the transcription factors
can alter expression of
genes necessary for cell
growth and DNA
synthesis.
Rachel A. Freiberg, Susannah L. Green, Amato J. Giaccia
Hypoxia and Cell Cycle
In: Cell Cycle Checkpoints and Cancer
Mikhail V. Blagosklonny, Ed.
ISBN: 1-58706-067-1
Human Papilloma Virus, HPV, perturbs the pRb checkpoint allowing cells to enter
S Phase under conditions that may not be optimal or safe for DNA synthesis or
cell replication.
Hoenil Jo, Jae Weon Kim, Implications of HPV infection in uterine cervical cancer,
Cancer Therapy 3: 419-434, 2005
Sequential phosporylation of Rb by cyclin/cdk complex inhibits the repressor activity of
pRb. The HPV E7 binds to the hypophosphorylated form of the pRb proteins. This binding
disrupts the complex between pRB & the cellular transcription factor E2F, resulting in the
liberation of E2F, which allows the cell to enter the S phase of the cell cycle.
p53: the second major checkpoint
p53, p21 & The Second Checkpoint
Robert A. Weinberg, How Cancer Arises, Scientific American 275(3):62-70,
September 1996.
Hypoxia, cellular exposure to reactive oxygen species, mitochondrial
damage, or direct damage of DNA by chemicals or radiation can stimulate
p53 actions that halt cell division, activate DNA repair mechanisms, &/or
stimulate the cell to undergo apoptosis (programmed cell death). This
protects the organism from clonal expansion of mutated cells.
Olivier Pluquet, Pierre Hainaut
Genotoxic and non-genotoxic pathways of p53 induction
Oncoserve Online, 2004
Oncoserve Online p53.mht
Hoenil Jo, Jae Weon Kim,
Implications of HPV infection in uterine cervical cancer
Cancer Therapy 3: 419-434, 2005
HPV infection also perturbs the
second, p53, checkpoint preventing
p53 from diverting cells with
damaged DNA toward cell cycle
arrest or cell death. Damaged cells
can then proliferate unchecked.
DNA damage induces p53 activation, leading to either cell
cycle arrest or apoptosis. The HPV E6 binds to E6-AP &
redirects it to p53, which results in the E6-AP-mediated
ubiquitination & rapid proteasomal degradation of p53.
RB/p53 Interactions To Regulate Cell Cycle & Apoptosis
Cell cycle transition from G1-S phase is mediated by Rb interactions with the E2F transcription factor
family, an important regulator of the cell cycle. Growth factors lead to phosphorylation of Rb in late G1
phase by cdk/cyclin. This is followed by release of E2F, allowing transcriptional activation of E2F target
genes; this promotes S-phase entry & cell proliferation. HPV E7 & Simian Virus 40 (SV40) promote
release of E2F from Rb. In contrast HPV E6 & the dominant negative, DN-p53 inhibit p53 activity leading
to cell proliferation.
Shehata, Cancer Cell International 2005 5:10 doi:10.1186/1475-2867-5-10
p53
Rb
Cell Cycle
Checkpoints
www.physiomicsplc.com/cell%20cycle%20model.htm
http://www.wellesley.edu/Chemistry/chem2
27/nucleicfunction/cancer/cancer.html
http://www.eurogene.org/etext/c
ancgen/lectures/Bernards.htm
http://www.fhcrc.org/science/education/courses/cancer
www-medchem.ch.cam.ac.uk/picture.html _course/basic/approaches/fundamentals/cellcycle.html
Summary of Cancer and Cell Cycle:
Carcinogenesis seems to be a multistage process where normal cells
progress to cancer through a gradual accumulation of genetic errors.
This has led to the hypothesis that cancer may be caused by mutations
that cause genetic instability.
Cell cycle controls, checkpoints, maintain the genetic stability of dividing
cells.
There are at least two important known checkpoints, located in G1/S
and G2/M involving tumor suppressors Rb and p53, respectively.
p53 is activated by DNA damage.
During carcinogenesis, these checkpoints fail to prevent abnormal cells
from going through the cell cycle.
Extracellular factors may alter the status of the pRb checkpoint &
thereby change transcriptional activities.
http://www.benbest.com/health/cancer.html
Disruption of the cell cycle can result in replication of cells with:
damaged DNA
increased susceptibility to further DNA damage
ability to avoid apoptosis
ability to avoid immune surveillance
activated telomerase
Proto-oncogene
Gene mutation, gene movement, or change
in regulatory sequences or position
Oncogene
transcription
Oncogene-Product
Mechanisms of DNA damage/mutation
chemical – reactive agents, reactive oxygen species, environmental agents
radiation
replication damage – translocations, deletions, insertions
viral insertion/excision
Oncogene: modified gene that is believed to cause cancer
The proto-oncogene can become an oncogene by a relatively small
modification of its original function. There are three basic activation types:
•A mutation within a proto-oncogene can cause a change in the protein structure, causing
•an increase in protein (enzyme) activity
•a loss of regulation (pRB)
•An increase in protein concentration, caused by
•an increase of protein expression (through misregulation)(BCL-2 with miRNA’s)
•an increase of protein stability, prolonging its existence and thus its activity in the cell
•a gene duplication (one type of chromosome abnormality), resulting in an
increased amount of protein in the cell
•A chromosomal translocation (another type of chromosome abnormality), causing
•an increased gene expression in the wrong cell type or at wrong times
•the expression of a constitutively active hybrid protein. This type of aberration in a
dividing stem cell in the bone marrow leads to adult leukemia (BCL-2 with t(14;18))
Apoptotic Pathways: All roads lead to mitochondria
•Extrinsic
•Extracellular signals cause intracellular changes
•Caspase activation (8), eventually leads to mitochondria
•Instrinsic
•Starts with signals within the cell
•Caspase activation (9 and 3), Cytochrome c release
BCL-2, a different kind of oncogene
BCL-2 was originally discovered in Follicular Lymphoma patients
a chromosomal translocation between chromosomes 14 and 18 placed
BCL-2 under constitutive control of Ig heavy chain
results: much BCL-2 protein is made all of the time in these cells
This was the first time where a mutation that caused a protein to be overexpressed
caused cancer (in the past only down-regulation models were known, like pRB)
In Chronic Leukemia BCL-2 is also overexpressed, despite the absence of t(14;18)
microRNAs are responsible for BCL-2 overexpression in these cancers
loss of mir15 and 16 cause uncontrolled BCL-2 protein expression
A
B
C
D
E
F
H2
FL-1 FL-2 H2
BCL-2
actin
•comparable to levels found in follicular lymphoma and H2 cells, which have a t(14;18)
Del Gaizo Moore, et al. JCI 2007
How does BCL-2 overexpression lead to cancer?
There are pro and anti-apoptotic proteins
those that promote and those that oppose cell death
BCL-2 is an anti-apoptotic protein
DNA damage, environmental stress, or other cellular stresses cause death signaling
molecules to be expressed.
These death signals are able to be bound up by BCL-2.
In a normal cell with regular amounts of BCL-2, the BCL-2 gets “full” of death signals
Easily and there are excess death molecules to trigger apoptosis
BUT, if a cell has extra BCL-2 then it can absorb ALL of the death molecules
thereby preventing cell death
- death signals
- other proteins bound to BCL-2
- cytochrome c
- BCL-2 protein
Normal
cell
Death
- BAX/BAK protein
BCL-2 overexpressing cell
Cancer
Genes often involved in cancer formation, are
hot-spots for primary or secondary mutations
Tumor Suppressors
Receptors
Transducers
Hormones
Transcription Factors
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DNA DAMAGE RESPONSE
First Printed in R&D Systems 2003 Catalog
The Process of Carcinogenesis
Cancer:
inappropriately controlled cell replication
leading to disruption of normal physiology,
metabolism or structure ultimately
disrupting homeostasis irreversibly
Neoplasm:
new cell growth; may be benign (not unlimited or
invasive) or malignant (cancerous leading toward
metastasis)
Hypertrophy – elevated size, for cell or tissue
Hyperplasia – elevated cell number
Path to Cancer:
Completion is rare due to endogenous controls & mechanisms!
Induction/Initiation/primary mutation
– fixation into the genome
-- avoidance of apoptosis
-- avoidance of immune rejection
Promotion
– stimulation of cell expansion of mutated clone
-- continued avoidance of apoptosis
-- continued avoidance of immune surveillance
Conversion/Transformation
-- epigenetic &/or secondary mutations
-- immortalization, activation of telomerase
-- loss of cell contact inhibition
-- angiogenesis of primary tumor
Progression
-- tertiary mutations
-- outgrowth of tumor
Metastases
-- breach of vascular endothelium
-- lodging & binding to capillary beds
-- invasion of secondary sites
Changes in Cancer
These range from the
molecular through cellular
& organ levels to the entire
organism. What begins in a
single cell, possibly even a
single alteration of one
chemical bond, ultimately
manifests as a terminal
physiological imbalance for
the host organism. This
might be termed the
“Butterfly Effect” in cancer.
Fabio Grizzi, Maurizio Chiriva-Internati,
Cancer: looking for simplicity and finding
complexity, Cancer Cell International
2006, 6:4, doi:10.1186/1475-2867-6-4.
Schematic of the route from a tissue stem cell through the
process of mutation & clonal expansion to malignancy
James E. Trosko, Randall J. Ruch, Cell-cell communication in carcinogenesis,
Frontiers in Bioscience, 3, d208-236, 2/15/1998.
Mathematical model of the route from a normal cell through
the various steps & processes leading to overt cancer
James E. Trosko, Randall J. Ruch, Cell-cell communication in carcinogenesis,
Frontiers in Bioscience, 3, d208-236, 2/15/1998.
Ball diagram of Nowell's hypothesis
Green balls represent cells that have developed a genetic abnormality & are expanding
or growing into a clone of cells. One of these cells develops a 2nd genetic abnormality,
blue ball. This then expands into its own clone of cells, subclones of the green
population. A third genetic mistake, dark red ball, leads to clonal expansion of a subsubclone. Eventually, a genetic mistake is made in one of the cells of the subclones or
sub-subclones that allows that cell to spin off a cancerous subclone.
http://www.barrettsinfo.com/content/5_how_does_cancer_develop_in_barretts.htm
The site was funded by AstraZeneca LP through an unrestricted educational grant to the
Ryan Hill Research Foundation, Seattle, WA
Another schematic of carcinogenesis emphasizes the early
steps in tumor formation including the role of cellular repair &
suppression of apoptosis but fails to note the importance of
secondary or tertiary mutations in allowing clonal expansion,
evasion of immune suppression, & establishment of unlimited
growth potential.
Where might those occur?
http://www.belleonline.com/n2v91.html
James E. Klaunig, Lisa M. Kamendulis, Yong Xu, Epigenetic Mechanisms of Chemical Carcinogenesis
Division of Toxicology, Department of Pharmacology and Toxicology, Indiana University School of Medicine,
Indianapolis, IN
Another schematic emphasizing the cellular stages
in carcinogenesis, cellular mutation, & agents that
may be involved in the various steps.
http://www2.scitech.sussex.ac.uk/undergrad/coursenotes/ehh/lec4/4.html
This depiction of the steps in the in vivo process
compares these changes with what occurs during the
in vitro transformation of cells grown in tissue culture.
Cell Transformation Assays as Predictors of Human Carcinogenicity
The Report and Recommendations of ECVAM Workshop 391-3
ATLA 27: 745-767
The upper row represents disturbances in growth, differentiation,
& tissue integrity that lead to the phenotypes that characterize
the different stages of cancer, shown in the lower row. Multiple
genetic alterations underlie cancer development, including
oncogene activation & tumor suppressor loss of function.
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Note that even in well developed experimental models
we still lack clear markers or unique triggers for the
Promotion & Progression stages of carcinogenesis.
Zbigniew Walaszek, Margaret Hanausek, Thomas J. Slaga, Combined natural source
inhibitors in skin cancer prevention, Cellscience Reviews 1(3), ISSN 1742-8130.
This description
comes a bit closer
to what has been
observed; there still
is obvious
discussion of which
molecular or cellular
events contribute
specifically to the
Promotion,
Progression,
Conversion/
Transformation,
Invasion/ Metastasis
steps.
The interaction of
carcinogens with
cells that can lead
cells toward
formation of
malignant tumors.
Note the multiple
points at which a
carcinogen or
cells damaged by a
carcinogen may be
eliminated or
repaired.
Tobacco smoking and cancer: The promise of molecular epidemiology
Sophia S. Wang, B.S., Jonathan M. Samet, M.D., M.S.
Salud Publica Mex 1997;39:331-345.
Carcinogen exposure is not simply the amount of compound
applied to an organism but the amount to which the reactive
molecules in target cells are exposed, moreover, multiple
steps of response are involved in activation of cancer.
http://www.iem.cas.cz/Data/Img/big/genetic_exotox_fig1.jpg
Department Of Genetic Ecotoxicology, Institute of Experimental Medicine,
Academy of Sciences of the Czech Republic
A correlation of the events in carcinogen
metabolism with the stages of cells moving
toward clinical disease
Tobacco smoking and cancer: The promise of molecular epidemiology
Sophia S. Wang, B.S., Jonathan M. Samet, M.D., M.S.
Salud Publica Mex 1997;39:331-345.
Besides losing the ability to
correctly determine if their
environment is appropriate for
division & the characteristics
necessary for the immune
system to remove them as
damaged cells, cells on the path
to tumor & cancer formation also
gain several capacities: they
evade apoptosis, produce their
own growth factors, become
insensitive to growth
suppressors & cell contact
signals, gain telomerase activity
& overcome the Hayflick limit, &
express angiogenic factors &
molecules needed during
metastasis.
Douglas Hanahan & Robert A. Weinberg,
The hallmarks of cancer,
Cell 100:57–70, 2000.
The multi-step nature of carcinogenesis is again emphasized
when chronic inflammation seems involved in initiation
Figure 1 Inflammatory-epithelial interactions in multi-step carcinogenesis
Moss SF and Blaser MJ (2005) Mechanisms of Disease: inflammation and the origins of cancer. Nat Clin Pract
Oncol 2: 90–97 10.1038/ncponc0081
The process also remains similar when chronic
infection with a viral agent, e.g., HPV is involved.
Céline Delloye, Elodie Gautier, Michèle Ottmann, Epidémiologie et oncogénèse
liées aux infections par les Papillomavirus, Virologie Etudiants M1 ENS Lyon.mht
Eva Szabo &
Gail L. Shaw
A Specific
Disease:
Lung Cancer
http://www.moffitt.usf.edu/pubs/ccj/v4n2/article1.html
Initiation
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Tumor
Suppressor
Genes as
Initiation
Targets
Mutation or deletion of tumor suppressor (TS) genes may initiate many forms of cancer. For tumors to
develop, both alleles of the TS gene must be inactivated. In familial cancer syndromes, a mutant allele of a
TS gene is inherited and is present in every cell (e.g. p53 in Li Fraumeni). But, tumorigenesis is not
initiated until the second allele is inactivated in a somatic cell. In non-familial cases, inactivation of both
alleles occurs via somatic mutation or deletion. The end result is the same in both cases, the lack of a
functional TS gene leads to tumor development.
Philadelphia Chromosome Formation:
Classic Case of Chromosomal Rearrangement in Carcinogenesis
Rearranged chromosomes: the c-abl
oncogene from the distal tip of
chromosome 9q34 when translocated to
the bcr (break-point cluster region)
locus on chromosome 22q11.2 forms the
t(9;22) translocation found in >95% of
CML, chronic myelogenous leukemia. It
generates a chimeric gene that
expresses a chimeric bcr-abl mRNA &
fusion protein that localizes to the
cytoplasm & remains constitutively
active in phosphorylating STAT-5 &
suppressing apoptosis.
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Promotion
Conversion, Transformation
Angiogenesis
Expression of angiogenic factors, e.g., VEGF forms, promote
vascularization of tumors & establish the routes by which
metastasis-capable tumor cells may reach the blood supply &
secondary tumor sites.
http://cancer.duke.edu/pated/PFRCNews/Pictures/angiogenesis.jpg
Receptor-binding specificity of VEGF family members & VEGFR-2
signalling pathways
The multitude of VEGF
forms along with the
number of available
receptors & linked
transduction pathways
demonstrate the wide
range of effects tumor
expression of these
factors may have on
both tumor cells & their
surrounding tissue cells.
Hiroyuki Takahashi, Masabumi Shibuya, The vascular endothelial growth factor (VEGF)/VEGF receptor
system and its role under physiological and pathological conditions, Clin. Sci. (2005) 109, 227-241
Clinical Science
www.clinsci.org
Events leading to angiogenesis and metastasis
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MMPs
Initial tumor,
distal to vasulature,
becomes hypoxic
Early tumors are small, <1 mm3 in diameter. Without angiogenesis tumors cannot grow further even
though active cell division counter-balanced by apoptosis continues to occur. Tumor cells most distal to
blood supply become hypoxic & produce hypoxia inducible factor-1α (HIF-1α) which accumulates in the
cytoplasm & translocates to cell nuclei. This promotes transcription of many target genes, including that
for vascular endothelial growth factor (VEGF). Thus, an angiogenic switch is activated that stimulates
formation of the new vascular necessary for tumor growth. Tumor cell/stromal cell/endothelial cell
interactions cause secretion & activation of matrix metallo-proteinases (MMPs) that degrade the
extracellular matrix and permit budding of new blood vessels from existing vessels. Proliferation &
migration of vascular endothelial cells are triggered by angiogenic factors secreted by tumor cells, such
as VEGF & basic fibroblast growth factor (bFGF). Blood vessels established within tumors permit invasion
of tumor cells into the bloodstream where they are carried to additional sites in the body. If they become
attached or lodged, & invade the local blood vessels, they may then establish new tumors or metastases.
Progression
Generation of the Mutator Phenotype in Oncogenesis
Possible Route to the Multiple Mutations Seen in Later Cancer Stages
Evolutionary Dynamics of Mutator Phenotypes in Cancer: Implications for Chemotherapy, Natalia L.
Komarova and Dominik Wodarz, 2003, Cancer Research, 63, 6635-6642. (Full text (HTML) and PDF
versions of the article are available on the Cancer Research website.) PubMed ID: 14583456
Hypothetical Model
of Chemoresistance
in Human Ovarian
Cancer Cells
Fraser et al. Reproductive
Biology and Endocrinology
2003 1:66
doi:10.1186/1477-7827-1-66
In chemosensitive ovarian cancer cells (A), cisplatin increases p53, leading to upregulation of proteins
promoting cell cycle arrest, e.g., p21, & pro-apoptotic proteins such as Bax & Fas. This activates both the
intrinsic (mitochondrial) & extrinsic (death-receptor) apoptotic paths with the overall result being activation of
the execution caspase-3 (& -7, not shown). In these cells, cell survival mediators such as Xiap, Akt, and Flip (in
red) are downregulated or are in their inactive state. Prohibitin may also play a role in inhibiting cell cycle
progression via the Rb-E2F pathway by binding Rb. In a chemoresistant cell (B), increased p53 ubiquitination by
MDM2 results in maintenance of low levels of p53, despite the presence of cisplatin. Also, cisplatin fails to
downregulate Xiap, thereby maintaining an active state of the PI3K/Akt pathway, & binding of TNFR2 by TNFα
leads to upregulation of FLIP through the NFκB pathway, thus inhibiting the pro-apoptotic actions of NFκB
through TNFR1. Overall, because the caspase cascade now fails to be activated by the chemotherapeutic agent,
these cells lose their capacity to undergo apoptosis. They have become chemoresistant.
Stages of tumour development
Malignant cell
Proliferation
Cytotoxics
Endocrine
EGFR inhibitors
HER2 antibodies
Angiogenesis
Antiangiogenics
Novel
agents
Vascular
targeting
agents Novel
agents
Invasion
Metastatic
Cancer
Invasion
Dissemination
of other organs
of other
organs
Neovascular
endothelial
maintenance
Carcinogenesis
Stages & Mechanisms:
Breast & Colon Cancer
Breast Cancer Continuum:
intervention possibilities
Prevention of Recurrence
Women at
Increased
Risk
PreMalignant
Conditions
1.7 % to
14%
LCIS 6.5%
ADH 5.1%
NonInvasive
Cancer
DCIS 7.2%
Prevention of Clinically
Detectable Breast Cancer
Tumors
< 1cm
11.8%
Early Stage
node neg
25.1%
Prevention of
Progression
Early Stage
node pos
47.1%
Prevention of Contralateral
Breast Cancer 3.2%
Late Stage
Cancer
Recurrence
of Breast
Cancer
Breast Cancer staging
With thanks to Professor W.Jonat
Breast Cancer staging 2
With thanks to Professor W.Jonat
Breast Cancer staging 3
With thanks to Professor W.Jonat
Staging Classification of Breast Tumour
OVEREXPRESSION OF p68 RNA HELICASE IN COLORECTAL TUMORS
We and others have shown that p68 RNA
helicase is overexpressed in colon cancer. In
particular, hyperplastic polyps which
eventually develop via adenomas into
malignant adenocarcinomas, are devoid of
significant p68 RNA helicase
immunostaining (see Figure).
However, adenomas as well as
adenocarcinomas show p68 RNA helicase
overexpression, suggesting that p68 RNA
helicase may contribute to the malignant
transformation of colon cells.
Janknecht Laboratory , Mayo Clinic
http://mayoresearch.mayo.edu/mayo/research/janknecht_lab/overexpression.cfm
Normal Arrangement of Elements of an Epithelium
The multiple layers between the epithelial cells & the vasculature
must be breached for a cancer to become metastatic.
Progression of Colon Cancer
National Cancer Institute
Video Links for Other Lectures or Film Loops on
Carcinogenesis, the Cell Cycle & Endocrinology
General Site (multiple films):
http://www.powershow.com/view/3ba793ODE2M/Normal_Cell_Cycle_Controls_powerpoint_ppt_presentation
Putting the Breaks on Cancer (Vogelstein, Johns Hopkins University):
http://media.hhmi.org/hl/03Lect1.html