Mutant p53: one name, many proteins
William A. Freed-Pastor and Carol Prives1
Department of Biological Sciences, Columbia University, New York, New York 10027, USA
There is now strong evidence that mutation not only
abrogates p53 tumor-suppressive functions, but in some
instances can also endow mutant proteins with novel
activities. Such neomorphic p53 proteins are capable of
dramatically altering tumor cell behavior, primarily
through their interactions with other cellular proteins
and regulation of cancer cell transcriptional programs.
Different missense mutations in p53 may confer unique
activities and thereby offer insight into the mutagenic
events that drive tumor progression. Here we review
mechanisms by which mutant p53 exerts its cellular
effects, with a particular focus on the burgeoning mutant
p53 transcriptome, and discuss the biological and clinical
consequences of mutant p53 gain of function.
The TP53 gene, which resides on chromosome 17p13.1
and encodes the p53 protein, is the most frequent target
for mutation in human cancer, with greater than half of
all tumors exhibiting mutation at this locus (Vogelstein
et al. 2000; Petitjean et al. 2007b). In this review, we
present an overview of the current understanding of the
significance of p53 mutations in cancer. At the outset, we
would like to point out that there are several excellent
reviews on this subject (Brosh and Rotter 2009; Kim et al.
2009; Oren and Rotter 2010; Goh et al. 2011; Goldstein
et al. 2011). Our goal is to provide an update on these
reviews, focusing in particular on the means by which
mutant p53 proteins regulate the gene expression pat-
terns of the tumor cells that they inhabit.
The discovery of the p53 ‘proto-oncogene’
The p53 protein was first identified in a complex with
the simian virus 40 (SV40) large T-antigen (Lane and
Crawford 1979; Linzer and Levine 1979). It was sub-
sequently demonstrated that many tumors produce abun-
dant levels of this protein, a phenomenon that was not
observed in normal tissue, suggesting that p53 might act
as a cellular oncogene (DeLeo et al. 1979; Rotter 1983).
This notion was reinforced when ectopic expression of
newly cloned p53 cDNAs was shown to cooperate with
oncogenic Ras to transform primary cells in culture
(Eliyahu et al. 1984; Parada et al. 1984). Furthermore,
overexpression of p53 was demonstrated to increase
tumorigenicity in otherwise p53-null cells (Wolf et al.
1984). Thus, throughout the first decade after its discov-
ery, p53 was generally acknowledged as a proto-oncogene
(Levine and Oren 2009).
However, multiple early findings called into question
the role of p53 as a pro-oncogenic factor. For example, the
murine Trp53 gene was shown to be inactivated by
retroviral insertions in several tumor models (Wolf and
Rotter 1984; Ben David et al. 1988). Discrepant findings
were reported regarding the ability of p53 to transform
primary cells, and when several groups compared the
sequences of their cloned p53 cDNAs, the striking result
was that each clone differed in sequence from the others
(Levine and Oren 2009). It was soon recognized that these
early experiments demonstrating that p53 overexpres-
sion could transform cells and promote in vivo tumor
growth were actually performed with mutated versions of
p53 that had been isolated from tumor cells (Hinds et al.
1989, 1990; Levine and Oren 2009). Thus, instead of
describing the function of wild-type p53, they were in
fact detailing the role of mutant p53 in tumor biology (the
importance of which becomes apparent below).
In 1989, seminal findings overturned the widely accepted
notion that p53 acts as a proto-oncogene. Vogelstein and
colleagues (Baker et al. 1989) investigated genetic alter-
ations in colorectal carcinomas and demonstrated that
>50% of these tumors exhibit loss of heterozygosity
(LOH), a hallmark of tumor suppressor genes, at the
TP53 locus (most commonly, mutation of one TP53
allele and deletion of the corresponding TP53 allele).
Work from Levine’s and Oren’s groups (Eliyahu et al.
1989; Finlay et al. 1989) demonstrated that overexpres-
sion of wild-type p53 was actually sufficient to suppress
oncogenic transformation. These and subsequent find-
ings described below firmly established p53 as a tumor
suppressor gene. Looking back, however, one should
never discount seemingly contradictory results. It turns
out that we can still gain deep insight into the role of p53
in tumor biology from these early ‘‘artifacts’’ studying
p53 and tumor suppression
Soon after this paradigm shift took place in the p53 field,
several studies served to confirm the role of wild-type p53
as a tumor suppressor and establish this protein as one
[Keywords: gain of function; mutant p53; oncogenic; p53; transcriptome;
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.190678.112.
1268GENES & DEVELOPMENT 26:1268–1286 ? 2012 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/12; www.genesdev.org
of the most important players in cancer biology. In the
late 1960s, a number of extremely cancer-prone families
were identified in the United States and Europe (Li and
Fraumeni 1969a,b). This familial cancer syndrome came
to be known as Li-Fraumeni syndrome (LFS), a rare
autosomal-dominant disorder that predisposes individ-
uals to breast cancer, sarcomas, and other neoplasms. LFS
was later shown to be caused by germline mutations in
TP53 (Malkin et al. 1990; Srivastava et al. 1990). A mouse
model in which p53 was disrupted by homologous re-
combination revealed that although p53?/?mice were
developmentally normal (for the most part), they were
extremely cancer-prone (Donehower et al. 1992; Attardi
and Jacks 1999). Mice devoid of p53 exhibited an extreme
susceptibility to developing tumors, primarily lympho-
mas and sarcomas, with three out of every four p53?/?
mice having developed at least one obvious neoplasm by
6 mo of age. In contrast, wild-type littermates failed to
develop any tumors by 9 mo of age. In addition to the
early findings by the Vogelstein group (Vogelstein et al.
2000; Petitjean et al. 2007b), literally thousands of studies
have now confirmed that TP53 mutations are not re-
stricted to colorectal cancer, but are present in >50% of
all human tumors, although the extent of p53 mutation
varies with the tumor type. It is now widely acknowl-
edged that p53 mutations are the most common genetic
event in human cancer (Levine and Oren 2009).
Indeed, it has been hypothesized that p53 function
is compromised in most human tumors (Polager and
Ginsberg 2009). While at least half of all tumors exhibit
mutation of p53, in those that retain wild-type p53, its
activity can be attenuated by several other mechanisms.
For example, many DNA tumor viruses encode proteins
that can inactivate p53; SV40 large T-antigen, adenovirus
E1B-55-kDa protein, and the E6 oncoprotein of human
papilloma virus (HPV) types 16 and 18 all bind to p53 and
inactivate its function (Levine 2009). The biological
relevance of these interactions is highlighted by the fact
that HPV types 16 and 18 have been implicated in cer-
vical carcinogenesis (Ferenczy and Franco 2002). Another
mechanism by which tumors inactivate p53 is through
the up-regulation or activation of negative regulators of
p53. Mdm2, an E3 ubiquitin ligase, is the major negative
regulator of p53 and serves to keep p53 levels in check
under unstressed conditions (Poyurovsky and Prives
2006; Manfredi 2010; Marine and Lozano 2010). Addi-
tionally, a homolog of Mdm2, MdmX (also known as
Mdm4), also serves as a negative regulator of p53 (Marine
et al. 2007). Not surprisingly, both Mdm2 and MdmX are
overexpressed in a variety of neoplasms (Marine et al.
Wild-type p53 has now secured its place as a critical
player in cancer biology, but before we move on to the role
of mutant p53 in tumors, it is important to briefly review
the current view of how p53 acts as a tumor suppressor.
Function of wild-type p53
Wild-type p53 can be activated by a number of cellular
stressors, including DNA damage, hypoxia, and oncogene
activation (Vousden and Lu 2002). Following activation,
wild-type p53 normally functions as a sequence-specific
transcription factor to inhibit cell cycle progression, pro-
mote senescence, or induce apoptotic cell death (Prives
and Hall 1999; Vousden and Lu 2002; Vousden and Prives
The p53 protein possesses an acidic N-terminal trans-
activation domain (now recognized to be two distinct
transactivation subdomains), a proline-rich domain, and
a centrally located sequence-specific DNA-binding do-
main, followed by an oligomerization domain and a basic
C-terminal regulatory domain (Fig. 1A; Laptenko and
Prives 2006). Wild-type p53 functions as a homotetramer
in cells, binding to p53 response elements composed of
two decamers separated by a spacer of 0–14 nucleotides
(59-RRRCWWGYYYn0–14RRRCWWGYYY-39) [(A) ade-
nine; (T) thymine; (C) cytosine; (G) guanine; (R) purine;
(Y) pyrimidine; (W) A/T; (n) any nucleotide] (el-Deiry et al.
1992; Funk et al. 1992; Riley et al. 2008). A myriad of
genes have been shown to be transcriptional targets of
wild-type human p53. The products of p53 target genes
mediate the downstream cellular outcomes of p53 acti-
vation such as cell cycle arrest (CDKN1A, MIR34A, etc.),
senescence (CDKN1A, PAI1, etc.), apoptosis (PUMA,
BAX, etc.), and metabolic processes (TIGAR, SCO2,
GLS2, etc.) (Prives and Hall 1999; Vousden and Lu 2002;
Riley et al. 2008; Vousden and Prives 2009; Vousden and
Each of these cellular outcomes has been shown to be
important for the tumor-suppressive ability of wild-type
p53. There is substantial evidence to support a role for
apoptosis in the tumor-suppressive function of p53. For
example, mice in which the proline-rich domain of p53
had been deleted (this mutant protein lacks the ability to
induce cell cycle arrest but retains the ability to induce
programmed cell death) are still efficiently protected
from spontaneous tumor development, suggesting that
the ability to induce apoptosis is critical to the tumor-
suppressive ability of p53 (Toledo et al. 2006). However,
a second mouse model argues that cell cycle arrest plays
at least a partial role in tumor-suppressive function: A
rare tumor-derived mutant of p53 (p53-R175P) was iden-
tified that can induce cell cycle arrest, but not apoptosis
(Rowan et al. 1996). (This nomenclature will be used
throughout this review. The first letter represents the
amino acid present in the wild-type protein, the number
represents the amino acid position number counting from
the N terminus, and the last letter represents the amino
acid present in the mutated protein. In this case, R175P
designates an arginine mutated to a proline at position
175 in the p53 protein.) Mice expressing the murine
equivalent to this p53 mutant (p53-R172P) demonstrate
a delay in spontaneous tumor formation, suggesting that
cell cycle arrest and chromosome stability also protect
against tumor development (Liu et al. 2004). Possibly all
p53 activities contribute to its ability to suppress tumor-
igenesis in different contexts. These and many other data
support the notion that wild-type p53 is unequivocally
a tumor suppressor. However, biology, it seems, is never
satisfied with a simple answer.
Mutant p53 activities and targets in cancer cells
GENES & DEVELOPMENT1269
Findings within the p53 field have emerged to help
explain many of the seemingly contradictory results from
the first decade of p53 research, when p53 was widely
considered to be an oncogene. Unlike most tumor sup-
pressor genes, which are predominantly inactivated as
a result of deletion or truncation (Weinberg 1991), the
vast majority of cancer-associated mutations in TP53 are
missense mutations, single base-pair substitutions that
result in the translation of a different amino acid in that
position in the context of the full-length protein. The
great majority of these missense mutations are clustered
within the central most conserved region of p53 that
spans the DNA-binding domain, and among these are
a small number (approximately six) of ‘‘hot spot’’ residues
that occur with unusually high frequency (Fig. 1A,B;
Harris and Hollstein 1993; Cho et al. 1994; Petitjean
et al. 2007a). This is in striking contrast to the majority of
tumor suppressors (examples include RB1, APC, NF1,
NF2, and VHL), the primary mutations in which are de-
letion or nonsense, leading to little or no expression of the
respective proteins (Levine et al. 1995). While wild-type
p53 under unstressed conditions is a very short-lived pro-
tein, these missense mutations lead to the production of
full-length altered p53 protein with a prolonged half-life
(Strano et al. 2007). Mutant p53 protein stability is dis-
cussed at greater length later in this review. Many of
these stable mutant forms of p53 can exert a dominant-
negative effect on the remaining wild-type allele, serving
to abrogate the ability of wild-type p53 to inhibit cellular
transformation, particularly when the mutant protein is
expressed in excess of its wild-type counterpart (Brosh
and Rotter 2009; Oren and Rotter 2010). Such dominant-
negative activity may be effected by either formation
of mutant/wild-type p53 cotetramers (Chan et al. 2004)
or the incorporation of wild-type p53 into mutant p53
supratetrameric aggregates (Xu et al. 2011). Importantly,
missense mutations in p53 in human tumors are usually
followed by LOH at the corresponding locus, suggesting
that there is a selective advantage conferred by losing
the remaining wild-type p53, even after one allele has
been mutated (Baker et al. 1990; Brosh and Rotter 2009).
These observations, among others, have led to the ‘‘gain-
of-function’’ hypothesis, which states that mutation of
TP53 is not equivalent to simply losing wild-type p53
function; rather, the strong selection for maintained ex-
pression of a select group of mutant p53 proteins suggests
a positive role for certain p53 mutants in tumorigenesis.
While inactivating missense mutations in p53 may
be selected for during tumor progression due to their
ability to act as dominant-negative inhibitors of wild-type
cers. (A) TP53 missense mutation data for human
cancer patients (N = 19,262) were obtained from the
p53 International Agency for Research on Cancer
(IARC) database and plotted as a function of amino
acid position. Schematic of the p53 protein with
domain structures illustrated. (TAD) Transactivation
domain (1–42); (PRD) proline-rich domain (40–92),
which also contains a second transactivation domain;
(DBD) DNA-binding domain (101–306); (OD) oligomer-
ization domain (307–355), also contains a nuclear ex-
port signal; (CTD) C-terminal regulatory domain (356–
393), also contains three nuclear localization signals
(data adapted from http://p53.free.fr). (B) Table for the
six ‘‘hot spot’’ residues in p53 with corresponding
frequency of any mutation at a given residue. TP53
mutation data for human cancer patients (N = 25,902)
were obtained from the p53 database (http://p53.free.fr).
(C) Table for the most common missense mutations at
‘‘hot spot’’ residues in p53 with corresponding fre-
quency of particular mutation. TP53 mutation data
for human cancer patients (N = 25,902) were obtained
from the p53 database (http://p53.free.fr).
TP53 mutational spectrum in human can-
Freed-Pastor and Prives
1270 GENES & DEVELOPMENT
Li FP, Fraumeni JF Jr. 1969b. Soft-tissue sarcomas, breast cancer,
and other neoplasms. A familial syndrome? Ann Intern Med
Li Y, Prives C. 2007. Are interactions with p63 and p73 involved
in mutant p53 gain of oncogenic function? Oncogene 26:
Li D, Marchenko ND, Moll UM. 2011a. SAHA shows preferen-
tial cytotoxicity in mutant p53 cancer cells by destabilizing
mutant p53 through inhibition of the HDAC6–Hsp90 chap-
erone axis. Cell Death Differ 18: 1904–1913.
Li D, Marchenko ND, Schulz R, Fischer V, Velasco-Hernandez
T, Talos F, Moll UM. 2011b. Functional inactivation of en-
dogenous MDM2 and CHIP by HSP90 causes aberrant sta-
bilization of mutant p53 in human cancer cells. Mol Cancer
Res 9: 577–588.
Lin J, Chen J, Elenbaas B, Levine AJ. 1994. Several hydropho-
bic amino acids in the p53 amino-terminal domain are
required for transcriptional activation, binding to mdm-2
and the adenovirus 5 E1B 55-kD protein. Genes Dev 8:
Lin J, Teresky AK, Levine AJ. 1995. Two critical hydrophobic
amino acids in the N-terminal domain of the p53 protein are
required for the gain of function phenotypes of human p53
mutants. Oncogene 10: 2387–2390.
Linzer DI, Levine AJ. 1979. Characterization of a 54K dalton
cellular SV40 tumor antigen present in SV40-transformed
cells and uninfected embryonal carcinoma cells. Cell 17: 43–
Liu G, McDonnell TJ, Montes de Oca Luna R, Kapoor M,
Mims B, El-Naggar AK, Lozano G. 2000. High metastatic
potential in mice inheriting a targeted p53 missense muta-
tion. Proc Natl Acad Sci 97: 4174–4179.
Liu G, Parant JM, LangG, Chau P, Chavez-Reyes A, El-Naggar AK,
Multani A, Chang S, Lozano G. 2004. Chromosome stability,
in the absence of apoptosis, is critical for suppression of
tumorigenesis in Trp53 mutant mice. Nat Genet 36: 63–68.
Liu K, Ling S, Lin WC. 2011. TopBP1 mediates mutant p53 gain
of function through NF-Y and p63/p73. Mol Cell Biol 31:
Ludes-Meyers JH, Subler MA, Shivakumar CV, Munoz RM,
Jiang P, Bigger JE, Brown DR, Deb SP, Deb S. 1996. Tran-
scriptional activation of the human epidermal growth factor
receptor promoter by human p53. Mol Cell Biol 16: 6009–
Luo JL, Yang Q, Tong WM, Hergenhahn M, Wang ZQ, Hollstein
M. 2001. Knock-in mice with a chimeric human/murine p53
gene develop normally and show wild-type p53 responses to
DNA damaging agents: A new biomedical research tool.
Oncogene 20: 320–328.
Machado-Silva A, Perrier S, Bourdon JC. 2010. p53 family
members in cancer diagnosis and treatment. Semin Cancer
Biol 20: 57–62.
Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH,
Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, et al. 1990.
Germ line p53 mutations in a familial syndrome of breast
cancer, sarcomas, and other neoplasms. Science 250: 1233–
Manfredi JJ. 2010. The Mdm2–p53 relationship evolves: Mdm2
swings both ways as an oncogene and a tumor suppressor.
Genes Dev 24: 1580–1589.
Marin MC, Jost CA, Brooks LA, Irwin MS, O’Nions J, Tidy JA,
James N, McGregor JM, Harwood CA, Yulug IG, et al. 2000.
A common polymorphism acts as an intragenic modifier of
mutant p53 behaviour. Nat Genet 25: 47–54.
Marine JC, Lozano G. 2010. Mdm2-mediated ubiquitylation:
p53 and beyond. Cell Death Differ 17: 93–102.
Marine JC, Francoz S, Maetens M, Wahl G, Toledo F, Lozano G.
2006. Keeping p53 in check: Essential and synergistic func-
tions of Mdm2 and Mdm4. Cell Death Differ 13: 927–934.
Marine JC, Dyer MA, Jochemsen AG. 2007. MDMX: From
bench to bedside. J Cell Sci 120: 371–378.
Matas D, Sigal A, Stambolsky P, Milyavsky M, Weisz L,
Schwartz D, Goldfinger N, Rotter V. 2001. Integrity of
the N-terminal transcription domain of p53 is required for
mutant p53 interference with drug-induced apoptosis.
EMBO J 20: 4163–4172.
Mizuno H, Spike BT, Wahl GM, Levine AJ. 2010. Inactivation of
p53 in breast cancers correlates with stem cell transcrip-
tional signatures. Proc Natl Acad Sci 107: 22745–22750.
Muller BF, Paulsen D, Deppert W. 1996. Specific binding of
MAR/SAR DNA-elements by mutant p53. Oncogene 12:
Muller PA, Caswell PT, Doyle B, Iwanicki MP, Tan EH, Karim S,
Lukashchuk N, Gillespie DA, Ludwig RL, Gosselin P, et al.
2009. Mutant p53 drives invasion by promoting integrin
recycling. Cell 139: 1327–1341.
Noll JE, Jeffery J, Al-Ejeh F, Kumar R, Khanna KK, Callen DF,
Neilsen PM. 2011. Mutant p53 drives multinucleation and
invasion through a process that is suppressed by ANKRD11.
Oncogene doi: 10.1038/onc.2011.456.
Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT,
Crowley D, Jacks T. 2004. Mutant p53 gain of function in
two mouse models of Li-Fraumeni syndrome. Cell 119: 847–
Olivier M, Langerod A, Carrieri P, Bergh J, Klaar S, Eyfjord J,
Theillet C, Rodriguez C, Lidereau R, Bieche I, et al. 2006.
The clinical value of somatic TP53 gene mutations in 1,794
patients with breast cancer. Clin Cancer Res 12: 1157–
Oren M, Rotter V. 2010. Mutant p53 gain-of-function in cancer.
Cold Spring Harb Perspect Biol 2: a001107. doi: 10.1101/
Parada LF, Land H, Weinberg RA, Wolf D, Rotter V. 1984.
Cooperation between gene encoding p53 tumour antigen
and ras in cellular transformation. Nature 312: 649–651.
Peart MJ, Prives C. 2006. Mutant p53 gain of function: The NF-Y
connection. Cancer Cell 10: 173–174.
Peng Y, Chen L, Li C, Lu W, Chen J. 2001. Inhibition of MDM2
by hsp90 contributes to mutant p53 stabilization. J Biol
Chem 276: 40583–40590.
Petitjean A, Achatz MI, Borresen-Dale AL, Hainaut P, Olivier M.
2007a. TP53 mutations in human cancers: Functional selec-
tion and impact on cancer prognosis and outcomes. Onco-
gene 26: 2157–2165.
Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P,
Olivier M. 2007b. Impact of mutant p53 functional proper-
ties on TP53 mutation patterns and tumor phenotype:
Lessons from recent developments in the IARC TP53 data-
base. Hum Mutat 28: 622–629.
Pietsch EC, Sykes SM, McMahon SB, Murphy ME. 2008. The
p53 family and programmed cell death. Oncogene 27: 6507–
Polager S, Ginsberg D. 2009. p53 and E2f: Partners in life and
death. Nat Rev Cancer 9: 738–748.
Poyurovsky MV, Prives C. 2006. Unleashing the power of p53:
Lessons from mice and men. Genes Dev 20: 125–131.
Preuss U, Kreutzfeld R, Scheidtmann KH. 2000. Tumor-derived
p53 mutant C174Y is a gain-of-function mutant which
activates the fos promoter and enhances colony formation.
Int J Cancer 88: 162–171.
Prives C, Hall PA. 1999. The p53 pathway. J Pathol 187: 112–
Freed-Pastor and Prives
1284GENES & DEVELOPMENT
Prives C, White E. 2008. Does control of mutant p53 by
Mdm2 complicate cancer therapy? Genes Dev 22: 1259–
Pugacheva EN, Ivanov AV, Kravchenko JE, Kopnin BP, Levine
AJ, Chumakov PM. 2002. Novel gain of function activity of
p53 mutants: Activation of the dUTPase gene expression
leading to resistance to 5-fluorouracil. Oncogene 21: 4595–
Resnick MA, Inga A. 2003. Functional mutants of the sequence-
specific transcription factor p53 and implications for master
genes of diversity. Proc Natl Acad Sci 100: 9934–9939.
Ribeiro RC, Sandrini F, Figueiredo B, Zambetti GP, Michalkiewicz
E, Lafferty AR, DeLacerda L, Rabin M, Cadwell C, Sampaio G,
et al. 2001. An inherited p53 mutation that contributes in
a tissue-specific manner to pediatric adrenal cortical carci-
noma. Proc Natl Acad Sci 98: 9330–9335.
Riley T, Sontag E, Chen P, Levine A. 2008. Transcriptional
control of human p53-regulated genes. Nat Rev Mol Cell Biol
Rippin TM, Bykov VJ, Freund SM, Selivanova G, Wiman KG,
Fersht AR. 2002. Characterization of the p53-rescue drug
CP-31398 in vitro and in living cells. Oncogene 21: 2119–
Rotter V. 1983. p53, a transformation-related cellular-encoded
protein, can be used as a biochemical marker for the de-
tection of primary mouse tumor cells. Proc Natl Acad Sci 80:
Rowan S, Ludwig RL, Haupt Y, Bates S, Lu X, Oren M,
Vousden KH. 1996. Specific loss of apoptotic but not cell-
cycle arrest function in a human tumor derived p53 mutant.
EMBO J 15: 827–838.
Sampath J, Sun D, Kidd VJ, Grenet J, Gandhi A, Shapiro LH,
Wang Q, Zambetti GP, Schuetz JD. 2001. Mutant p53 co-
operates with ETS and selectively up-regulates human
MDR1 not MRP1. J Biol Chem 276: 39359–39367.
Sankala H, Vaughan C, Wang J, Deb S, Graves PR. 2011.
Upregulation of the mitochondrial transport protein, Tim50,
by mutant p53 contributes to cell growth and chemo-
resistance. Arch Biochem Biophys 512: 52–60.
Sarig R, Rivlin N, Brosh R, Bornstein C, Kamer I, Ezra O,
Molchadsky A, Goldfinger N, Brenner O, Rotter V. 2010.
Mutant p53 facilitates somatic cell reprogramming and
augments the malignant potential of reprogrammed cells.
J Exp Med 207: 2127–2140.
Scian MJ, Stagliano KE, Deb D, Ellis MA, Carchman EH, Das A,
Valerie K, Deb SP, Deb S. 2004. Tumor-derived p53 mutants
induce oncogenesis by transactivating growth-promoting
genes. Oncogene 23: 4430–4443.
Scian MJ, Stagliano KE, Anderson MA, Hassan S, Bowman M,
Miles MF, Deb SP, Deb S. 2005. Tumor-derived p53 mutants
induce NF-kB2 gene expression. Mol Cell Biol 25: 10097–
Selivanova G, Iotsova V, Okan I, Fritsche M, Strom M, Groner B,
Grafstrom RC, Wiman KG. 1997. Restoration of the growth
suppression function of mutant p53 by a synthetic peptide
derived from the p53 C-terminal domain. Nat Med 3: 632–
Sepehrnia B, Paz IB, Dasgupta G, Momand J. 1996. Heat shock
protein 84 forms a complex with mutant p53 protein pre-
dominantly within a cytoplasmic compartment of the cell.
J Biol Chem 271: 15084–15090.
Shvarts A, Steegenga WT, Riteco N, van Laar T, Dekker P,
Bazuine M, van Ham RC, van der Houven van Oordt W,
Hateboer G, van der Eb AJ, et al. 1996. MDMX: A novel p53-
binding protein with some functional properties of MDM2.
EMBO J 15: 5349–5357.
Sigal A, Rotter V. 2000. Oncogenic mutations of the p53 tumor
suppressor: The demons of the guardian of the genome.
Cancer Res 60: 6788–6793.
Singer S, Ehemann V, Brauckhoff A, Keith M, Vreden S,
Schirmacher P, Breuhahn K. 2007. Protumorigenic overex-
pression of stathmin/Op18 by gain-of-function mutation in
p53 in human hepatocarcinogenesis. Hepatology 46: 759–
Song H, Hollstein M, Xu Y. 2007. p53 gain-of-function cancer
mutants induce genetic instability by inactivating ATM. Nat
Cell Biol 9: 573–580.
Soussi T, Lozano G. 2005. p53 mutation heterogeneity in
cancer. Biochem Biophys Res Commun 331: 834–842.
Srivastava S, Zou ZQ, Pirollo K, Blattner W, Chang EH. 1990.
Germ-line transmission of a mutated p53 gene in a cancer-
prone family with Li-Fraumeni syndrome. Nature 348: 747–
Staib F, Hussain SP, Hofseth LJ, Wang XW, Harris CC. 2003.
TP53 and liver carcinogenesis. Hum Mutat 21: 201–
Stambolsky P, Tabach Y, Fontemaggi G, Weisz L, Maor-Aloni R,
Siegfried Z, Shiff I, Kogan I, Shay M, Kalo E, et al. 2010.
Modulation of the vitamin D3 response by cancer-associated
mutant p53. Cancer Cell 17: 273–285.
Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A,
Oren M, Sudol M, Cesareni G, Blandino G. 2001. Physical
interaction with Yes-associated protein enhances p73 tran-
scriptional activity. J Biol Chem 276: 15164–15173.
Strano S, Fontemaggi G, Costanzo A, Rizzo MG, Monti O,
Baccarini A, Del Sal G, Levrero M, Sacchi A, Oren M, et al.
2002. Physical interaction with human tumor-derived p53
mutants inhibits p63 activities. J Biol Chem 277: 18817–
Strano S, Dell’Orso S, Di Agostino S, Fontemaggi G, Sacchi A,
Blandino G. 2007. Mutant p53: An oncogenic transcription
factor. Oncogene 26: 2212–2219.
Strauss BE, Haas M. 1995. The region 39 to the major transcrip-
tional start site of the MDR1 downstream promoter medi-
ates activation by a subset of mutant P53 proteins. Biochem
Biophys Res Commun 217: 333–340.
Suad O, Rozenberg H, Brosh R, Diskin-Posner Y, Kessler N,
Shimon LJ, Frolow F, Liran A, Rotter V, Shakked Z. 2009.
Structural basis of restoring sequence-specific DNA binding
and transactivation to mutant p53 by suppressor mutations.
J Mol Biol 385: 249–265.
Sugikawa E, Hosoi T, Yazaki N, Gamanuma M, Nakanishi N,
Ohashi M. 1999. Mutant p53 mediated induction of cell
cycle arrest and apoptosis at G1 phase by 9-hydroxyellipti-
cine. Anticancer Res 19: 3099–3108.
Suh YA, Post SM, Elizondo-Fraire AC, Maccio DR, Jackson JG,
El-Naggar AK, Van Pelt C, Terzian T, Lozano G. 2011. Mul-
tiple stress signals activate mutant p53 in vivo. Cancer Res
Sun Y, Cheung JM, Martel-Pelletier J, Pelletier JP, Wenger L,
Altman RD, Howell DS, Cheung HS. 2000. Wild type and
mutant p53 differentially regulate the gene expression of
human collagenase-3 (hMMP-13). J Biol Chem 275: 11327–
Terzian T, Suh YA, Iwakuma T, Post SM, Neumann M, Lang
GA, Van Pelt CS, Lozano G. 2008. The inherent instability of
mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes
Dev 22: 1337–1344.
Teufel DP, Freund SM, Bycroft M, Fersht AR. 2007. Four
domains of p300 each bind tightly to a sequence spanning
both transactivation subdomains of p53. Proc Natl Acad Sci
Mutant p53 activities and targets in cancer cells
GENES & DEVELOPMENT 1285
Toledo F, Krummel KA, Lee CJ, Liu CW, Rodewald LW, Tang M,
Wahl GM. 2006. A mouse p53 mutant lacking the proline-
rich domain rescues Mdm4 deficiency and provides insight
into the Mdm2–Mdm4–p53 regulatory network. Cancer Cell
Torgeman A, Mor-Vaknin N, Zelin E, Ben-Aroya Z, Lochelt M,
Flugel RM, Aboud M. 2001. Sp1–p53 heterocomplex me-
diates activation of HTLV-I long terminal repeat by 12-
O-tetradecanoylphorbol-13-acetate that is antagonized by
protein kinase C. Virology 281: 10–20.
Toyooka S, Tsuda T, Gazdar AF. 2003. The TP53 gene, to-
bacco exposure, and lung cancer. Hum Mutat 21: 229–
Vaughan CA, Singh S, Windle B, Sankala HM, Graves PR,
Andrew Yeudall W, Deb SP, Deb S. 2012. p53 mutants induce
transcription of NF-kB2 in H1299 cells through CBP and
STAT binding on the NF-kB2 promoter and gain of function
activity. Arch Biochem Biophys 518: 79–88.
Venot C, Maratrat M, Sierra V, Conseiller E, Debussche L. 1999.
Definition of a p53 transactivation function-deficient mu-
tant and characterization of two independent p53 trans-
activation subdomains. Oncogene 18: 2405–2410.
Vogelstein B, Lane D, Levine AJ. 2000. Surfing the p53 network.
Nature 408: 307–310.
Vousden KH, Lu X. 2002. Live or let die: The cell’s response to
p53. Nat Rev Cancer 2: 594–604.
Vousden KH, Prives C. 2009. Blinded by the light: The growing
complexity of p53. Cell 137: 413–431.
Vousden KH, Ryan KM. 2009. p53 and metabolism. Nat Rev
Cancer 9: 691–700.
Vu BT, Vassilev L. 2011. Small-molecule inhibitors of the p53–
MDM2 interaction. Curr Top Microbiol Immunol 348: 151–
Walker KK, Levine AJ. 1996. Identification of a novel p53 func-
tional domain that is necessary for efficient growth suppres-
sion. Proc Natl Acad Sci 93: 15335–15340.
Wang XJ, Greenhalgh DA, Jiang A, He D, Zhong L, Medina D,
Brinkley BR, Roop DR. 1998. Expression of a p53 mutant in
the epidermis of transgenic mice accelerates chemical car-
cinogenesis. Oncogene 17: 35–45.
Wang Y, Suh YA, Fuller MY, Jackson JG, Xiong S, Terzian T,
Quintas-Cardama A, Bankson JA, El-Naggar AK, Lozano G.
2011. Restoring expression of wild-type p53 suppresses
tumor growth but does not cause tumor regression in mice
with a p53 missense mutation. J Clin Invest 121: 893–904.
Weinberg RA. 1991. Tumor suppressor genes. Science 254:
Weisz L, Zalcenstein A, Stambolsky P, Cohen Y, Goldfinger N,
Oren M, Rotter V. 2004. Transactivation of the EGR1 gene
contributes to mutant p53 gain of function. Cancer Res 64:
Weisz L, Damalas A, Liontos M, Karakaidos P, Fontemaggi G,
Maor-Aloni R, Kalis M, Levrero M, Strano S, Gorgoulis VG,
et al. 2007a. Mutant p53 enhances nuclear factor kB activa-
tion by tumor necrosis factor a in cancer cells. Cancer Res
Weisz L, Oren M, Rotter V. 2007b. Transcription regulation by
mutant p53. Oncogene 26: 2202–2211.
Werner H, Karnieli E, Rauscher FJ, LeRoith D. 1996. Wild-type
and mutant p53 differentially regulate transcription of the
insulin-like growth factor I receptor gene. Proc Natl Acad Sci
Will K, Warnecke G, Wiesmuller L, Deppert W. 1998. Specific
interaction of mutant p53 with regions of matrix attachment
region DNA elements (MARs) with a high potential for base-
unpairing. Proc Natl Acad Sci 95: 13681–13686.
Wiman KG. 2010. Pharmacological reactivation of mutant p53:
From protein structure to the cancer patient. Oncogene 29:
Wolf D, Rotter V. 1984. Inactivation of p53 gene expression by
an insertion of Moloney murine leukemia virus-like DNA
sequences. Mol Cell Biol 4: 1402–1410.
Wolf D, Harris N, Rotter V. 1984. Reconstitution of p53 ex-
pression in a nonproducer Ab-MuLV-transformed cell line by
transfection of a functional p53 gene. Cell 38: 119–126.
Wong KB, DeDecker BS, Freund SM, Proctor MR, Bycroft M,
Fersht AR. 1999. Hot-spot mutants of p53 core domain evince
characteristic local structural changes. Proc Natl Acad Sci 96:
Wong WW, Dimitroulakos J, Minden MD, Penn LZ. 2002.
HMG-CoA reductase inhibitors and the malignant cell:
The statin family of drugs as triggers of tumor-specific
apoptosis. Leukemia 16: 508–519.
Xu J, Reumers J, Couceiro JR, De Smet F, Gallardo R, Rudyak S,
Cornelis A, Rozenski J, Zwolinska A, Marine JC, et al. 2011.
Gain of function of mutant p53 by coaggregation with
multiple tumor suppressors. Nat Chem Biol 7: 285–295.
Xue W, Zender L, Miething C, Dickins RA, Hernando E,
Krizhanovsky V, Cordon-Cardo C, Lowe SW. 2007. Senes-
cence and tumour clearance is triggered by p53 restoration in
murine liver carcinomas. Nature 445: 656–660.
Yan W, Chen X. 2009. Identification of GRO1 as a critical de-
terminant for mutant p53 gain of function. J Biol Chem 284:
Yan W, Chen X. 2010. Characterization of functional domains
necessary for mutant p53 gain of function. J Biol Chem 285:
Yoshikawa K, Hamada J, Tada M, Kameyama T, Nakagawa K,
Suzuki Y, Ikawa M, Hassan NM, Kitagawa Y, Moriuchi T.
2010. Mutant p53 R248Q but not R248W enhances in vitro
invasiveness of human lung cancer NCI-H1299 cells.
Biomed Res 31: 401–411.
Zhu J, Zhou W, Jiang J, Chen X. 1998. Identification of a novel
p53 functional domain that is necessary for mediating
apoptosis. J Biol Chem 273: 13030–13036.
Freed-Pastor and Prives
1286GENES & DEVELOPMENT