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Vol. 273, Issue 1, 1-4, January 2, 1998
From the Department of Molecular Biology, The Lerner Research
Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195
Loss of control of genomic
stability is central in the development of cancer, and p53, by
regulating normal responses to DNA damage and other forms of genotoxic
stress, is a key element in maintaining genomic stability. Thus, it is
no surprise that functional p53 is lost in about half of all human
cancers. What about the other half? One possibility is that
p53-independent regulatory mechanisms have been lost. Another is that
inactivation of p53-dependent pathways can occur at any of
several different points and that p53 itself is merely the most common
target. For example, the p53 inhibitor Mdm2 is overexpressed in tumors
independently of the p53 mutation. Here, we review pathways that signal
in to p53, in response to different forms of stress, and
pathways that signal out, triggered by activated p53. It is
clear that p53 is the central component of a complex network of
signaling pathways and that the other components of these pathways pose
alternative targets for inactivation. For additional recent reviews,
see Refs. 1 and 2.
The amount of p53 protein increases in response to a variety of
signals, such as damaged DNA, arrest of DNA or RNA synthesis, or
nucleotide depletion. The same stimuli also activate p53, which is
mostly latent in the absence of stress. The increase in the amount of
protein is often achieved through an increase in the half-life, from
~30 min in untreated cells to ~150 min in, for example, UV-treated
cells (3). However, an increase in the rate of translational initiation
of p53 mRNA can also affect the steady-state level of the protein
(for example, see Ref. 4). The ubiquitin pathway probably plays an
important role in degrading p53 (5), and evidence for a
ubiquitin-independent mechanism of degradation has also been presented
(6).
Recent evidence has also shown that the Mdm2 protein, which binds to
p53, accelerates its degradation, possibly through the ubiquitin
pathway (7, 8). The fact that the mdm2 gene is a
transcriptional target of p53 suggests a molecular basis for the
commonly observed increased metabolic half-life of mutant p53 proteins
defective in transactivation. Thus, the stability of these mutant
proteins appears to be due to their inability to up-regulate the
expression of Mdm2, a protein involved in their degradation, rather
than an intrinsic property conferring resistance to degradation
per se.
An increase in transactivation due to p53, with no increase in the
level of the protein, was found in cells treated with low doses of UV
radiation, and microinjection of an antibody to the C-terminal domain
also stimulated p53-dependent transcription, even in the
absence of DNA damage (9). Chernov and Stark (10) found that sodium
salicylate, which inhibits protein kinases inhibits the activation of
p53, with no significant effect on the accumulation of the protein.
Several processes might be involved in activating p53 (1), including
phosphorylation, glycosylation, binding to regulatory proteins,
alternative splicing, and acetylation (11).
How does p53 sense signals? Several known proteins are suspects. The
DNA-dependent protein kinase
(DNAPK),1 a plausible
candidate, binds to and is activated by broken ends of DNA (12) and can
phosphorylate residues 15 and 37 of p53 in a DNA-dependent
manner in vitro (13). The phosphorylation of serine 15 affects the transactivation and growth arrest functions of p53 in some
cells (14). However, cells lacking DNAPK show no defect in the
p53-mediated inhibition of the cell cycle, revealing that if DNAPK has
any role in regulating p53 at all, other components must be able to
compensate for its loss (15).
Many protein kinases have been shown to phosphorylate p53 in
vitro and are candidates for upstream regulators (1). However, very little in vivo evidence exists for the role of
phosphorylation in regulating p53. Recent work showing that p53 can be
acetylated in vitro is intriguing and suggests the
possibility of an additional mechanism of regulation (11). However, it
is still necessary to show that acetylation occurs in response to
stress.
Poly(ADP-ribose) polymerase (PARP) has long been known to have a role
in recognizing DNA damage and in DNA repair. PARP-null Chinese hamster
cells are defective in activating p53 and resistant to apoptosis
induced by DNA damage (16). However, embryo fibroblasts from PARP-null
mice have normal DNA repair and DNA damage-induced apoptosis (17), and
although there is a significant decrease in the induction of p53
protein after DNA damage or nucleotide depletion, there is no change in
p53 activity or in the cellular responses to stress (18). Therefore,
although PARP is involved in increasing the amount of p53 protein in
mouse fibroblasts, other signaling pathways must be more important in
activating p53 in response to DNA damage, consistent with experiments
showing at least two levels of 53 regulation (9, 10). Loss of ATM, the
product of the ataxia telangiectasia gene, slows the induction of p53
protein in response to the DNA strand breaks caused by Recently a role for oncogenic Ras and the mitogen-activated protein
(MAP) kinase pathway in p53 modulation and function has been revealed
in both human and rodent cells. High expression of Ras or activation of
the Mos/MAPK pathway induces wild-type p53 levels and causes a
permanent growth arrest, similar to cellular senescence (24, 25). Cells
lacking p53 can tolerate high levels of MAPK and display loss of
p53-dependent cell cycle arrest and enhanced genomic
instability (24). In a cell line defective in the MAP kinase pathway
and in p53 expression, increased expression of the MAP kinase ERK2
restores the normal levels of p53, clearly placing ERK2 in a pathway
that regulates the steady-state level of
p53.3 MAPK has been shown to
phosphorylate residue 73 or 83 of murine p53 in vitro, and
this phosphorylation may be important in stabilizing the protein (26).
Other kinases, such as DNAPK II, cyclin A-Cdc2, and cyclin B-Cdc2, are
known to phosphorylate the p53 protein in vitro and may play
a role in stabilizing it (14, 27). The mechanisms of p53 induction in
response to different types of stress are still largely unknown.
p53 is involved in several different aspects of cell cycle arrest,
apoptosis, control of genome integrity, and DNA repair (1, 2). How does
it regulate so many different processes? p53 is a tetramer that can
bind to specific sequences and thus transactivate a group of genes
(reviewed in Ref. 1; for example, p21/waf1,
gadd45, mdm2, cyclin G,
bax, and IGF-BP3). Several groups have found that
active p53 is sensed differently at different promoters, resulting in
differential DNA binding and transactivation (for example, see Ref.
28). p53 can also inhibit the expression of some genes (for example,
see topoisomerase IIa (29)). Furthermore, some
p53-dependent phenotypes do not involve transcriptional
regulation at all (for example, see Ref. 30).
Cell Cycle Controls
The G1-S Transition--
Antibodies recognizing the C
terminus of p53 prevent serum-stimulated fibroblasts from entering S
phase (31). This result, originally interpreted as evidence that a
positive function of p53 was required, posed a paradox when
overexpression of wild-type p53 was found to cause growth arrest (32).
The paradox was resolved when it was found that these antibodies
activate rather than inhibit p53 (9). It is now understood more clearly
that p53 mediates G1 arrest in response to DNA damage
caused by UV or The Spindle Checkpoint--
p53 is involved in a checkpoint that
blocks the re-replication of DNA when the mitotic spindle has been
damaged. When the DNA content of embryo fibroblasts was measured after
treatment with nocodazole or other inhibitors of microtubule assembly,
it was found that normal fibroblasts arrest with a 4 N
content of DNA, whereas p53-null fibroblasts attain DNA contents of 8 or 16 N (40). Spindle destruction might block progression
through mitosis, or re-replication might be controlled by blocking
entry into S phase. In a murine cell line with wild-type p53,
nocodazole causes transient mitotic arrest, followed by entry into
G1 without chromosome segregation (41). p53 is induced
after mitosis is complete. The conclusion that the p53 induced in
response to spindle damage blocks entry into S phase was also reached
by analyzing DNA synthesis in fibroblasts exposed to nocodazole or
colcemid (42). Interestingly, fibroblasts from p21/Waf1-null
mice do not re-replicate their DNA when treated with spindle poisons, consistent with the observation that G1 arrest in response
to a number of agents is only partially abrogated in these cells (43).
Therefore, p53 must also utilize p21-independent mechanisms to arrest
cells in G1 and thus to inhibit re-replication in response to spindle poisons.
Centrosome Homeostasis--
Embryo fibroblasts from p53-null mice
acquire more than two centrosomes, leading to mitosis with more than
two spindle poles and frequent mitotic failure (44). p53 is associated
with centrosomes and thus may affect centrosome duplication directly
(45). Alternatively, improper duplication of centrosomes may signal p53
activation, which could in turn cause arrest in G2 or
G1. It is intriguing that MAP kinase and Cdc2, both capable
of phosphorylating p53, are also bound to centrosomes (1, 26, 46, 47)
and, like p53, MAP kinase is important for centrosome homeostasis
(46).
The G2-M Transition--
In both human and mouse
fibroblasts, overexpression of wild-type p53 can inhibit entry into
mitosis (48, 49). Recent results show that this property of p53 is
important in a novel cell cycle checkpoint that controls entry into
mitosis when DNA synthesis is
blocked.4 In
hydroxyurea-treated cells in which synthesis of dNTPs is blocked very
rapidly, p53 plays a vital role in inhibiting premature entry into
mitosis. Wild-type mouse embryo fibroblasts do not attempt mitosis in
hydroxyurea. In contrast, p53-null mouse embryo fibroblasts continue to
attempt mitosis, entering metaphase with condensed chromatin and high
levels of phosphorylated histone H1. However, cytokinesis cannot occur
and mitosis is aborted, presumably because the spindles cannot
segregate incompletely replicated DNA. Presumably, these responses are
present to prevent the segregation of damaged or incompletely
synthesized DNA.
Regulation of Apoptosis
p53 plays a role in triggering apoptosis in certain cell types,
e.g. cells of hematopoietic origin. Stimuli such as DNA
damage, withdrawal of growth factors, and expression of Myc or E1A can also cause p53-dependent apoptosis (50-54). p53 must be
able to function as a transcription factor to block the
G1-S transition, but p53-mediated apoptosis does not
necessarily require transcriptional activation, because inhibition of
transcription by actinomycin D or translation by cycloheximide does not
always affect p53-dependent apoptosis (30, 54).
Furthermore, inhibitors of protein phosphatases induce
p53-dependent apoptosis in the absence of
transactivation (55). However, the pro-apoptotic proteins Bax and
Igf-Bp3 are transcriptional targets of p53, suggesting that
transactivation by p53 is important in inducing apoptosis in some
circumstances. In addition, the anti-apoptotic proteins Bcl2 and the
adenovirus 19-kDa E1B protein can prevent p53-mediated
apoptosis (53, 56).
p53 induces apoptosis in some cell types but cell cycle arrest in
others, in response to the same stimulus. Although the mechanisms of
such divergent responses are not known, deletion of p21/Waf1 can cause cells that would otherwise undergo p53-dependent
cell cycle arrest to undergo apoptosis instead, underscoring the major role of genetic background in determining these cellular responses (57). Several variables, such as the extent of DNA damage and the
levels of p53, also affect the choice between cell cycle arrest and
apoptosis (58). Also, cross-talk between the p53 and Rb pathways may be
important in determining the biological responses to DNA damage. For
example, the inactivation of Rb results in the loss of G1
arrest and induction of apoptosis after DNA damage (59). This might be
explained by the release of E2F (Fig. 1), which when overexpressed on
its own can induce apoptosis (60). Furthermore, overexpression of Rb
blocks p53-mediated apoptosis (61). Thus, modulation of Rb and E2F
through p53 signaling in response to DNA damage may play a central role
in determining the balance between cell cycle arrest and apoptosis.
Genomic Stability
p53-dependent cell cycle control maintains genetic
integrity in populations of cells. Gene amplification is a widely used model to study genetic integrity. In most transformed or immortalized cells, drugs such as PALA or methotrexate, which inhibit the synthesis of nucleotide precursors, select for the amplification of target genes
whose products overcome the inhibition, carbamyl-P synthetase/aspartate transcarbamylase/dihydro-orotase (CAD) in the case of PALA and dihydrofolate reductase for methotrexate (62). However, normal cells
(63) and rare cell lines, such as REF52 (64), do not give rise to
resistant colonies in these drugs. The function of p53 is lost
frequently during the process of tumorigenesis (65) and in the
spontaneous immortalization of primary cells (66), indicating that p53
can be the main factor determining permissivity for gene amplification.
Indeed, embryo fibroblasts from p53-null mice are permissive for gene
amplification (67), and primary human cells from Li-Fraumeni patients
became permissive as soon as they lost their single copy of wild-type
p53 (67, 68). Transformation of REF52 cells with either SV40 large T
antigen or activated Ras plus E1A abolishes p53-dependent
cell cycle control and allows these cells to become permissive for gene
amplification (64). What signal is generated as a part of the mechanism
of gene amplification that could activate p53-dependent
pathways and prevent the propagation of drug-resistant cells? The
current model of amplification involves, as an essential early step,
multiple bridge-breakage-fusion cycles in which broken DNA is formed
throughout an entire lineage of daughter cells (69, 70). The importance of DNA damage in regulating early stages of gene amplification was
demonstrated with REF52 cells transfected with a temperature-sensitive mutant of SV40 large T antigen (71). When these cells are selected with
PALA at low temperature, active large T antigen inactivates p53,
rendering the cells permissive for gene amplification. Restoration of
p53 by inactivating large T antigen at a higher temperature very early
in the process of forming PALA-resistant colonies stably arrests all
cells containing newly amplified DNA.
Human cell lines can achieve resistance to PALA by mechanisms other
than gene amplification in situ, which is by far the most common mechanism in rodent cells. Most PALA-resistant colonies, from
several different human cell lines, either do not contain amplified CAD
DNA at all or increase the copy number of CAD as isochromosomes 2p
(72). However, in both cases, p53-dependent pathways are
still involved. The depletion of pyrimidine nucleotides caused by PALA
generates a signal for p53 induction before any DNA damage occurs (35),
arresting the cells and preventing PALA-resistant colonies from
forming. Recent work has shown that overexpressing endogenous or
exogenous N-Myc allows REF52 cells to overcome the p53-dependent cell cycle arrest caused by DNA damage,
making these cells permissive for gene amplification (73). This
observation emphasizes the fact that p53-dependent pathways
can be inhibited at any of several different points (Fig. 1).
Concluding Remarks
p53 signaling pathways connect with tumor suppressors and
oncogenes known to influence the cell cycle machinery (Fig. 1). Alterations in components either upstream or downstream of p53 may be
analogous to inactivation of p53 itself, preventing all or a part of
the entire pathway from functioning and leading to deregulation of cell
cycle controls, genomic instability, and the development of cancer. In
addition, the recently discovered protein p73, which has a high degree
of structural and functional homology to p53, may be another important
target for inactivation during the development of cancer (74). It
remains to be determined if p73 affects signals impinging on or
emanating from p53 or if it is a central component of its own
independent signaling network.
*
This minireview will be reprinted
in the 1997 Minireview Compendium, which
will be available in December, 1997. This work was supported by National Institutes of
Health Grant GM49345.
1
The abbreviations used are: DNAPK,
DNA-dependent protein kinase; PARP, poly(ADP-ribose)
polymerase; PALA,
N-(phosphonacetyl)-L-aspartate; NBS, Nijmegen
breakage syndrome; MAP, mitogen-activated protein; MAPK, MAP kinase;
CAD, carbamyl-P synthetase/aspartate
transcarbamylase/dihydro-orotase.
2
M. L. Agarwal and G. R. Stark,
unpublished results.
3
M. L. Agarwal, R. Chilakamarti, W. R. Taylor, A. Agarwal, and G. R. Stark, manuscript in
preparation.
4
W. R. Taylor, M. L. Agarwal, A. Agarwal, D. W. Stacey, and G. R. Stark, submitted for
publication.
MINIREVIEW
The p53 Network*
INTRODUCTION
Top
Introduction
References
Signaling In
-radiation
but not in response to the pyrimidine dimers caused by UV radiation
(19, 20). Similarly, p53 is induced normally in human
ATM-null cells after treatment with
N-(phosphonacetyl)-L-aspartate (PALA), which
blocks de novo UMP biosynthesis, or adriamycin, which
damages DNA.2 p53 and ATM may
both be components of complexes that function in recombination (21).
Similarly, the gene product involved in Nijmegen breakage syndrome
(NBS) has also been placed upstream of p53 in the pathway that responds
to ionizing radiation but not in the responses to other DNA-damaging
agents (22). Because the defects in p53 induction in
ATM-null, NBS-null, and PARP-null cells are partial or selective for certain kinds of DNA damage, these
gene products are involved in some but not all of the signals. Double or triple knock-outs should have a more profound (perhaps even a
complete) defect in p53 induction in response to DNA damage. Similar
partial defects in p53 signaling have been observed in Fanconi anemia
syndrome (FAS) and Bloom's syndrome (BLS) fibroblasts, suggesting that
many pathways regulate p53 (20, 23).
Signaling Out
-radiation, chemotherapeutic drugs, or nucleotide
deprivation (33-35). The cell-type variability in
p53-dependent G1 arrest is illustrated by
studies with -radiation, which in normal diploid fibroblasts causes
long-term, p53-dependent arrest associated with prolonged induction of p21/Waf1 (36). The irreversibility of this arrest depends
on the inability of these cells to repair even a small number of
double-strand DNA breaks, so that the activating signal persists (37).
In contrast, -irradiation of HT1080 cells, derived from a
fibrosarcoma with wild-type p53, causes a transient G1 arrest (38), whereas the colorectal tumor line RKO and the breast tumor
line MCF7, which also have wild-type p53, fail to arrest in
G1 following irradiation (39). These differences may
indicate that tumor formation may involve the inactivation of
components upstream or downstream of p53, causing the cellular response
to DNA damage to fail. For example, -irradiation activates p53 to turn on the transcription of p21/Waf1, which binds to and
inhibits cyclin-dependent kinases, causing
hypophosphorylation of Rb, thus preventing the release of E2F and
blocking the G1-S transition (Fig.
1). Alteration of any of these downstream
components may have an effect similar to that of inactivating p53
itself in preventing the pathway from functioning.
View larger version (31K):
[in a new window]
Fig. 1.
Components of p53 signaling pathways.
p53 accumulates and is modified and activated in response to signals
generated by a variety of genotoxic stresses. Several proteins,
including ATM, PARP, FAS, BLS, and NBS (see the text for full names),
are involved in activation, but the pathways that lead to modification are largely unknown. The RAS-MAP kinase pathway is involved in establishing basal levels of p53 and may also affect function. Some of
the cellular functions affected by p53 can be compromised by
deregulated expression of Myc, Bcl2, E1B, or E2F. The control of p53
activity includes an autoregulatory loop involving Mdm2. The intact set
of p53-dependent pathways helps to maintain genomic integrity by eliminating damaged cells, either by arresting them permanently or through apoptosis. p53 also helps to regulate entry into
mitosis, spindle formation, and centrosome integrity, cell cycle
checkpoints that are likely to be involved in preventing DNA damage
from occurring.
FOOTNOTES
To whom correspondence should be addressed: Dept. of Molecular
Biology, The Lerner Research Inst., The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-3900; Fax: 216-444-3279; E-mail: starkg2cesmtp.ccf.org.
REFERENCES
Top
Introduction
References
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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