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GREAT EXPERIMENTS
p53 is a tumor suppressor gene
Arnold Levine
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Introduction
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In the 1960s, the origins of cancer in humans remained a mystery, with the notable
exception of four observations made over the previous 60 years:
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- cancer could be caused by viruses
in at least some animal species;
- cancer could also be caused by selected
chemicals, as demonstrated in animal models;
- some cancers showed an inherited
component in both animals and some human families;
- the incidence of cancer in humans
was known to rise exponentially as a function of age.
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The problem, from the perspective of the 1960s, was whether these four observations
were related, and if so, how. In addition, it was not clear which of these "facts"
applied to humans and which were only applicable to animal models.
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For the molecular biologists of the time, viruses were attractive experimental systems.
They were relatively simple, each with only a few genes, and bacterial viruses were
understood in some detail. Two classes of animal viruses, the DNA and RNA tumor
viruses, were known to produce tumors in animals, and a large number of laboratories
began to study these viruses. By the mid-1970s, the RNA tumor viruses led to the
discovery of oncogenes in viruses and their normal counterparts in the host. During
this same period carcinogenic chemicals had been demonstrated to have their effects
by acting as mutagens. These observations united the roles of viruses, genes, and
chemicals in the possible origin of human cancers: mutant versions of normal genes,
whether due to viral infection or chemical mutagenesis of endogenous genes, provided
a genetic basis for cancer.
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Shortly after the elucidation of the role of oncogenes, a second class of genes,
called recessive oncogenes and also known as anti-oncogenes or tumor suppressor
genes, were inferred to exist from several experimental approaches. In the 1980s,
these genes were identified, cloned, and their modes of action and functions identified.
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Our work on tumor suppressors began with the study of SV40, a small DNA tumor virus,
known to be able to initiate tumors when injected into hamsters. Viral proteins
expressed in these tumors cause the production of antibodies against the viral "tumor
antigens." These antibodies also recognize "fetal antigens," proteins specifically
expressed during fetal development (i.e. carcinoembryonic antigen and alpha fetal
protein). The expression of similar antigens after viral infection and during normal
development led to the idea that tumor cells might represent an undifferentiated
cellular state comparable to that of fetal cells. Infection of most murine cells
with SV40 results in the production of the viral proteins, large T antigen and small
t antigen. However, SV40 infected embryonal carcinoma (EC) cells (derived from a
tumor of the germ cell lineage), have a block to viral early gene expression and
do not express these tumor antigens. In 1978-79, Dan Linzer, a graduate student
in my laboratory, was studying the nature of this restriction of viral expression
in EC cells, in hopes of gaining some insight into how SV40 regulated cell proliferation.
What he found was a cellular protein that associated with SV40 large T antigen.
The p53 protein thus first came to attention as a tumor antigen, a protein recognized
by antibodies made by animals with tumors. Then, through the literature, it rapidly
graduated to become a putative oncogene. Finally, upon more detailed analyses, its
role as a tumor suppressor gene emerged and its critical function in human cancers
has now become clear (see Tumor suppressor p53 suppresses growth or triggers apoptosis).
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p53 associates with SV40 T antigen
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Figure 1
Immunoprecipitations were performed on fibroblasts or embryonal carcinoma (EC)
cells that were either SV40-infected or mock-infected. Sera from hamsters with SV40
induced tumors (T) or normal hamster serum (N) was used for the immunoprecipitations.
After infection of fibroblasts with SV40, tumor serum co-immunoprecipitates SV40
T antigen (94 kd) and p53 (lane 1) suggesting complex formation between these proteins
after viral infection. p53 is immunoprecipitated by tumor serum in either S(54
kd) V40 infected (lanes 5 and 9) or mock infected (lanes 7 and 11) EC cells, suggesting
that p53 is a cellular protein.
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In Dan's experiments, antisera from hamsters with SV40-induced tumors was collected.
This antisera was then used to search for antigens expressed in murine fibroblasts
or EC cells that were either SV40 infected or mock infected. As shown in Figure
1, the antibodies immunoprecipitated large T antigen from SV40 infected or transformed
murine fibroblasts, along with a protein of 54,000 daltons (later renamed p53).
These proteins were not found using normal sera or fibroblasts without SV40 infection
(1537). When testing the EC cell lines F9 and PCC-4, the SV40 tumor serum
immunoprecipitated a protein of the same 54 kDa size after SV40 infection, but surprisingly,
also immunoprecipitated the protein even in the absence of SV40 infection
(Figure 1) (1537). That this protein could be detected in the absence of
SV40 infection in EC cells strongly suggested that it was a cellular protein which
was bound by large T antigen after infection. Partial peptide maps of the 54 kDa
protein from the SV40 infected cells and the noninfected EC cell lines showed that
they were identical proteins, and that neither was a degradation product of T antigen.
At the time this work was published, Lane and Crawford (1536) found the
same protein, p53, in SV40 transformed cells and showed that p53 was complexed with
the SV40 T-antigen. The association of the cellular p53 protein with the T antigen
suggested that it might be important in cellular transformation, but at the time
its specific role was unknown.
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Shortly after these experiments were performed, Moshe Oren joined my laboratory
as a postdoctoral fellow and we decided to clone the cDNA for p53. Moshe immunoprecipitated
polysomes with a monoclonal antibody to p53 to enrich for pools of p53 mRNAs. cDNA
clones were identified that specifically hybridized to pools of cDNA probes made
from p53 immunoselected mRNAs and not to those made from unselected mRNAs. To confirm
the identity of cDNA clones derived from this procedure, Moshe used hybrid selection:
he hybridized total mRNA to the candidate cDNA, and then eluted the bound mRNA and
translated it in vitro. Antisera to p53 was used to detect the synthesized
p53 protein. Moshe obtained a partial cDNA clone after returning to Israel for a
position at the Weizmann Institute (1538). He sent us this clone and our
groups independently isolated full length clones. In collaboration with my lab,
Diane Pennica at Genentech picked out a full length cDNA clone from a F9 cell (EC
cells) library (1539).
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When we compared p53 amino acid sequences between our clone and Moshe's clone, we
noted a difference in only one out of the 390 residues of the full length protein:
his clone had a valine at position 135 while ours had an alanine at the same position.
At the time, no one thought much about this difference and chalked it up to either
a sequencing error or a polymorphism. In fact, this difference would be the basis
for a dramatic plot twist in the unfolding story of p53's functional role.
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p53 as a putative oncogene
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Figure 2
p53 as a putative oncogene. Numbers indicate number of foci. (Results from 1533.)
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Once we had the full length clones, the obvious next experiment was to see if the
p53 cDNA had oncogenic activity. Land and Weinberg had shown that transformation
of primary rat fibroblasts required two oncogenes, either myc plus ras,
or E1A plus ras. In these assays, transformed cells are easily visualized
as clusters of cells called foci that overgrow themonolayer of normal cells. Moshe's
laboratory readily showed that his p53 clone plus ras could also transform primary
rat embryo cells (1533), as illustrated in Figure 2, a result that suggested
that p53 was an oncogene. Indeed, another independent publication at the time also
came to this conclusion (1534). However, in contrast to these results,
Cathy Finlay in my laboratory could not reproduce this finding with our own cDNA
clone; we could only reproduce it when we used Moshe's clone. So how could we reconcile
these results?
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- we had the wild type p53 clone (which
did not cause transformation) and Moshe had a mutant (which did
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- conversely, Moshe had the wild type
cDNA which transformed cells via overexpression, and we had a mutant clone that
failed to do so;
- or the Val/Ala difference at position
135 was a splice variant (as no one had the entire gene this was a possibility)
or a polymorphism that gave different phenotypes when overexpressed in cells, as
in these transformation assays.
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Regardless of which of these possibilities proved to be right, it was clear at the
time that the story was not quite as simple as it had seemed initially.
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p53 as a tumor suppressor gene
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Figure 3
p53 as a suppressor of transformation. (Results from 873.)
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To approach the problem, we made a number of mutations in our cDNA clone and found
that many of these mutants, including the linker insertion mutant p53 KH215, transformed
cells when transfected together with ras(1540). This work, and
the sequences from a number of independently derived clones, strongly suggested
that our clone might be the wild type version of p53. Consistent with earlier data,
when we tested our clone and Moshe's side by side, ours (p53 wt) did not cause transformation
with ras, but Moshe's (p53 Val135) did, as did the p53 KH215 mutant, as
illustrated in Figure 3.
Importantly, the transformation seen with Moshe's p53 clone plus ras, was
suppressed by the addition of our cDNA in triple transfections. These results provided
an interpretation that could resolve much of the previous data. p53 was known to
exist as a tetramer and mutant p53 proteins were known to be capable of forming
complexes with wild-type p53. Thus, p53 mutants could act in a trans-dominant
fashion, causing transformation by complexing with, and inactivating, the endogenous
wild type rat p53 in the primary rat fibroblasts used for the transformation assays.
Introduction of our wild type clone in addition to Moshe's mutant clone would tip
the balance of wild type to mutant p53; with more wild type p53, the trans-dominant
effect of the mutant p53 clone would be blocked. Thus, co-expression of our wild
type clone resulted in an overall reduction of transformation caused by the mutant
clone.
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In addition to its effects on transformation due to mutant p53, our cDNA also prevented
myc plus ras transformation, or E1A plus ras transformation (Figure 3)
(873). It was only rarely that triple transfectants with
E1A plus ras plus our wild type p53 cDNA gave rise to foci of transformed cells.
When they did appear, in each case, the cells no longer expressed functional, wild-type
p53 (873). This result strongly suggested that transformation required
the inactivation of p53. On the basis of these results, we concluded that p53 was
not an oncogene, as it had originally been proclaimed to be, but rather
that it had exactly the opposite function, as a suppressor of transformation.
Moshe and his group published the same conclusion at about the same time (1535).
In retrospect, the use of a mutant version of p53, which was thought to
be wild-type, led to an initial conclusion that turned out to be 180° from the truth.
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Just as we had written this work up for publication, I presented it at a Cold Spring
Harbor Banbury meeting where Bert Vogelstein reported important results that were
entirely consistent with our conclusions. He and his colleagues found mutations
in both alleles of the p53 gene in three human colon cancers (1567). The
biallelic inactivation of a gene in human cancer is one of the hallmark features
of a tumor suppressor gene.
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The legacy
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Figure 4
The p53 pathway.
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Since the time p53 was found to be an anti-oncogene, we now know that it is a transcriptional
activator, and that upregulation of transcriptional target genes is important for
its tumor suppressor function (see p53 is a DNA-binding protein). We also
know a good deal about the upstream regulators of p53 and its downstream effects
and effectors, as summarized in Figure 4. p53 can be induced in response to a variety of cellular stresses
such DNA damage, low ribonucleoside triphosphate pools or activation of oncogenes,
such as myc or E1A. The result of p53 activation by these events is cell cycle arrest,
senescence or apoptosis. For example, in response to oncogene activation by mutation
in a tumor cell, wild-type p53 can mediate cellular apoptosis, killing the cell,
and thus serving to protect from tumor formation. This tumor suppressive effect
of wild-type p53 thus provides strong selective pressure for tumor cells to mutate
p53 for their survival. In cultured cells, the oncogenes myc or E1A can also activate
p53 for apoptosis (via the regulatory proteins p19ARF and MDM-2) and wild type p53
kills those cells (354). In fact, during the course of their immortalization,
most permanent mouse cell lines develop mutations in p53 (or the p53 pathway). In
retrospect, we were therefore very lucky to have chosen F9 cells for cloning p53.
Unlike most tumors, teratocarcinomas, the tumors from which F9 cells are derived,
do not select for p53 mutations (but inactivate the protein by another,
unknown mechanism); thus our F9 library fortunately contained wild-type p53.
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In ten years of research from 1979 to 1989, p53 has evolved from a tumor antigen
to an oncogene to a tumor suppressor gene. We now know that about 50%-55% of all
human tumors have mutations in the p53 gene. A second tumor suppressor gene, the
retinoblastoma susceptibility gene (Rb), encodes a protein that regulates the entry
of cells from G1 to S phase in the cell cycle. Like the p53 pathway, the Rb pathway
is also frequently mutated in human cancers, underscoring the importance of both
these pathways in regulating cellular proliferation and the need to inactivate them
during the course of tumorigenesis. Indeed, the small DNA tumor viruses SV40, the
adenoviruses and the human papilloma viruses have evolved mechanisms to abrogate
function of both these pathways. Thanks to a large body of work over the past 30
years, we now know many of the important players in the origins of cancer in humans.
In addition to the tumor suppressor proteins p53 and Rb, these include, enzymes
involved in DNA repair pathways, the telomere replicating enzyme telomerase and
the products of numerous other oncogenes.
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Based upon these discoveries, we now understand the observations made in the first
60-70 years of the last century. Some viruses cause cancer by carrying activated,
mutated oncogenes or by activating oncogenes in cells. Other viruses cause cancer
by inactivating tumor suppressor genes and their proteins. The chemical carcinogens
alter these genes directly via mutation. Inherited predispositions arise via germ
line mutations in tumor suppressor genes or defective genes in DNA repair pathways.
And finally, because cancers arise from mutations in multiple oncogenes and tumor
suppressor genes in the same cell, cancers are predominantly diseases of the elderly.
A lifetime of accumulated mutations in somatic tissues increases the incidence of
cancer as a function of age. The relationships between the apparently disparate
observations of the 1960s have been connected into one coherent hypothesis. It will
now be important to continue testing these ideas and challenging our assumptions.
The goal is now to develop a rational approach to therapy using our new-found information.
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The author
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Dr. Arnold J. Levine was President of The Rockefeller University from December,
1998 until February 2002. Dr. Levine was previously at Princeton University where
he was the Harry C. Weiss Professor in the Life Sciences. From 1984 to 1996, he
served as chairman of the department of molecular biology. In addition, Dr. Levine
was the chairman of the 1996 review panel on federal AIDS research funding.
Born in Brooklyn, Dr. Levine received a B.A. from Harpur College, SUNY, in 1961
and a Ph.D. from the University of Pennsylvania in 1966. After a postdoctoral fellowship
at the California Institute of Technology, he joined Princeton in 1968 as an assistant
professor and become a professor of biochemistry in 1976. In 1979, Dr. Levine moved
to the SUNY Stony Brook School of Medicine to chair the department of microbiology.
He returned to Princeton in 1984.
Dr. Levine has served on numerous scientific and medical advisory boards including
those of the Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center,
and the Whitehead Institute. He is also a former trustee of the University of Pennsylvania
and the Cold Spring Harbor Laboratory. Dr. Levine was elected to the National Academy
of Sciences in 1991 and to its Institute of Medicine in 1995. He has been the recipient
of numerous prestigious awards and prizes, and many honorary degrees. Dr. Levine
is the author of the book Viruses, published in 1992 by Scientific American
Library.
Arnold J. Levine
Rockefeller University
1230 York Ave.
New York, NY 10021
Phone: 212 327 8104
Fax: 212 327 8505
E-mail: alevine@rockvax.rockefeller.edu
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Last Revised on September 10, 2004
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J. (1989). The p53 proto-oncogene can act as a suppressor of transformation.
Cell 57, 1083-1093. PubMed Journal
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focus formation. Proc. Natl. Acad. Sci. USA 86, 8763-8767. PubMed
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antigen is bound to a host protein in SV40-transformed cells. Nature 278,
261-263. PubMed
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A. J. (1979). The SV40 A gene product is required for the production of a
54,000 MW cellular tumor antigen. Virology 98, 308-318. PubMed
- 1538 Oren, M. and Levine, A. J. (1983). Molecular
cloning of a cDNA specific for the murine p53 cellular tumor antigen. Proc.
Natl. Acad. Sci. USA 80, 56-59. PubMed
- 1539 Pennica, D., Goeddel, D. V., Hayflick, J.
S., Reich, N. C., Anderson, C. W., and Levine, A. J. (1984). The amino acid
sequence of murine p53 determined from a c-DNA clone. Virology 134, 477-482.
PubMed
- 1540 Finlay, C. A., Hinds, P. W., Tan, T. H.,
Eliyahu, D., Oren, M., and Levine, A. J. (1988). Activating mutations for
transformation by p53 produce a gene product that forms an hsc70-p53 complex with
an altered half-life. Mol. Cell Biol. 8, 531-539. PubMed
- 1567 Nigro, J. M. et al. (1989). Mutations
in the p53 gene occur in diverse human tumour types. Nature 342, 705-708.
PubMed Journal
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©Jones and Bartlett Publishers (2007)
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