Fine-structure of p53 (draft 090423d)
Kurt Kohn 23 April 2009
The numbers refer to the amino acid positions in the p53 fine-structure diagram.
E.g. “S9” means serine-9”.
1-43: activation domain (O'Keefe et al., 2003) - fig 1A
S9: phosphorylation site
S9 is phosphorylated by DNA-PK.
(Soubeyrand et al., 2004)
S15: phosphorylation site
Phosphorylation at multiple sites within the N-terminus of p53 promotes its
dissociation from hdm2/mdm2 and stimulates its transcriptional regulatory
potential. The large phosphoinositide 3-kinase-like kinases [ATM and ATR]
promote phosphorylation of human p53 at Ser15 and Ser20, and are required for
the activation of p53 following DNA damage. (DNA-PK) is another large
phosphoinositide 3-kinase-like kinase with the potential to phosphorylate p53 at
Ser15, and has been proposed to enhance phosphorylation of these sites in vivo.
Moreover, recent studies support a role for DNA-PK in the regulation of p53mediated apoptosis. We have shown previously that colocalization of p53 and
DNA-PK to structured single-stranded DNA dramatically enhances the potential
for p53 phosphorylation by DNA-PK. We report here the identification of p53
phosphorylation at two novel sites for DNA-PK, Thr18 and Ser9. Colocalization of
p53 and DNA-PK on structured DNA was required for efficient phosphorylation of
p53 at multiple sites, while specific recognition of Ser9 and Thr18 appeared to be
dependent upon additional determinants of p53 beyond the N-terminal 65 amino
acids. Our results suggest a role for DNA-PK in the modulation of p53 activity
resultant from the convergence of p53 and DNA-PK on structured DNA.
(Soubeyrand et al., 2004)
Here, we show that an MAR binding protein SMAR1 interacts with MDM2 and the
Ser15 phosphorylated form of p53, forming a ternary complex in the post stressrecovery phase. This triple complex formation between p53, MDM2 and SMAR1
results in recruitment of HDAC1 to deacetylate p53. The deacetylated p53 binds
poorly to the target promoter (p21), which results in switching off the p53
response, essential for re-entry into the cell cycle. Interestingly, the knock-down
of SMAR1 using siRNA leads to a prolonged cell-cycle arrest in the post stress
recovery phase due to ablation of p53-MDM2-HDAC1 interaction. Thus, the
results presented here for the first time highlight the role of SMAR1 in masking
the active phosphorylation site of p53, enabling the deacetylation of p53 by
HDAC1-MDM2 complex, thereby regulating the p53 transcriptional response
during stress rescue.
(Pavithra et al., 2009)
Here we delineate the minimal domain of SMAR1 (the arginine-serine-rich
domain) that is phosphorylated by protein kinase C family proteins and is
responsible for p53 interaction, activation, and stabilization within the nucleus.
SMAR1-mediated stabilization of p53 is brought about by inhibiting Mdm2mediated degradation of p53. We also demonstrate that this arginine-serine
(RS)-rich domain triggers the various cell cycle modulating proteins that decide
cell fate. Furthermore, phenotypic knock-down experiments using small
interfering RNA showed that SMAR1 is required for activation and nuclear
retention of p53. The level of phosphorylated p53 was significantly increased in
the thymus of SMAR1 transgenic mice, showing in vivo significance of SMAR1
expression. This is the first report that demonstrates the mechanism of action of
the MAR-binding protein SMAR1 in modulating the activity of p53, often referred
to as the "guardian of the genome."
(Jalota et al., 2005)
S18: phosphorylation site
S18 is phosphorylated by DNA-PK.
(Soubeyrand et al., 2004)
S20: phosphorylation site
Chk1 & Chk2 phosphorylate S20 and abrogate binding between p53 and Mdm2
(Brooks and Gu, 2003).
19-26: binding motif for Mdm2 or Mdmx
The crystal structure of the 109-residue amino-terminal domain of MDM2 bound
to a 15-residue transactivation domain peptide of p53 revealed that MDM2 has a
deep hydrophobic cleft on which the p53 peptide binds as an amphipathic alpha
helix. The interface relies on the steric complementarity between the MDM2 cleft
and the hydrophobic face of the p53 alpha helix and, in particular, on a triad of
p53 amino acids-Phe19, Trp23, and Leu26-which insert deep into the MDM2
cleft. These same p53 residues are also involved in transactivation, supporting
the hypothesis that MDM2 inactivates p53 by concealing its transactivation
domain. The structure also suggests that the amphipathic alpha helix may be a
common structural motif in the binding of a diverse family of transactivation
factors to the TATA-binding protein-associated factors.
(Kussie et al., 1996),(Rosal et al., 2004)
The primary contacts of the α-helical p53 peptide to Mdmx are
made by its hydrophobic Phe19, Trp23 and Leu26 that form together
an interface that is complementary to and fills up a hydrophobic pocket
of Mdmx (Fig. 1).
(Popowicz et al., 2008)
S20: phosphorylation site
ATM, ATR, and DNA-PK phosphorylate S20.
(Soubeyrand et al., 2004)
S46: phosphorylation site
Phosphorylation of p53 at Ser(46) is important to activate the apoptotic program.
Here, we report that ionizing radiation (IR) provokes homeodomain-interacting
protein kinase 2 (HIPK2) accumulation, activation, and complex formation with
p53. IR-induced HIPK2 up-regulation strictly correlates with p53 Ser(46)
phosphorylation. Down-regulation of HIPK2 by RNA interference specifically
inhibits IR-induced phosphorylation of p53 at Ser(46). Moreover, we show that
HIPK2 activation after IR is regulated by the DNA damage checkpoint kinase
ataxia telangiectasia mutated (ATM). Cells from ataxia telangiectasia patients
show defects in HIPK2 accumulation. Concordantly, IR-induced HIPK2
accumulation is blocked by pharmacologic inhibition of ATM. Furthermore, ATM
down-regulation by RNA interference inhibited IR-induced HIPK2 accumulation,
whereas checkpoint kinase 2 deficiency showed no effect. Taken together, our
findings indicate that HIPK2 is the IR-activated p53 Ser(46) kinase and is
regulated by ATM.
(Dauth et al., 2007)
Phosphorylation of p53 at Ser 46 was shown to regulate p53 apoptotic activity.
Here we demonstrate that homeodomain-interacting protein kinase-2 (HIPK2), a
member of a novel family of nuclear serine/threonine kinases, binds to and
activates p53 by directly phosphorylating it at Ser 46. HIPK2 localizes with p53
and PML-3 into the nuclear bodies and is activated after irradiation with
ultraviolet. Antisense inhibition of HIPK2 expression reduces the ultravioletinduced apoptosis. Furthermore, HIPK2 and p53 cooperate in the activation of
p53-dependent transcription and apoptotic pathways. These data define a new
functional interaction between p53 and HIPK2 that results in the targeted
subcellular localization of p53 and initiation of apoptosis.
(D'Orazi et al., 2002)
Phosphorylated S46 binds phosphorylated WOX1
WW domain-containing oxidoreductase WOX1, also named WWOX or FOR,
undergoes Tyr33 phosphorylation at its first N-terminal WW domain and
subsequent nuclear translocation in response to sex steroid hormones and stress
stimuli. The activated WOX1 binds tumor suppressor p53, and both proteins may
induce apoptosis synergistically. Functional suppression of WOX1 by antisense
mRNA or a dominant negative abolishes p53-mediated apoptosis. Here, we
determined that UV light, anisomycin, etoposide, and hypoxic stress rapidly
induced phosphorylation of p53 at Ser46 and WOX1 at Tyr33 (phospho-WOX1)
and their binding interactions in several tested cancer cells. Mapping by yeast
two-hybrid analysis and co-immunoprecipitation showed that phospho-WOX1
physically interacted with Ser46-phosphorylated p53. Knockdown of WOX1
protein expression by small interfering RNA resulted in L929 fibroblast resistance
to apoptosis by tumor necrosis factor, staurosporine, UV light, and ectopic p53,
indicating an essential role of WOX1 in stress stimuli-induced apoptosis. Notably,
UV light could not induce p53 protein expression in these WOX1 knockdown
cells, although p53 mRNA levels were not reduced. Suppression of WOX1 by
dominant negative WOX1 (to block Tyr33 phosphorylation) also abolished UV
light-induced p53 protein expression. Time course analysis showed that the
stability of ectopic wild type p53, tagged with DsRed, was decreased in WOX1
knockdown cells. Inhibition of MDM2 by nutlin-3 increased the binding of p53 and
WOX1 and stability of p53. Together, our data show that WOX1 plays a critical
role in conferring cellular sensitivity to apoptotic stress and that Tyr33
phosphorylation in WOX1 is essential for binding and stabilizing Ser46phosphorylated p53.
(Chang et al., 2005)
S46 phosphorylation facilitates K382 acetylation by CBP
Here we demonstrate that the human serine/threonine kinase homeodomaininteracting protein kinase-2 (HIPK2) colocalizes and interacts with p53 and
CREB-binding protein (CBP) within promyelocytic leukaemia (PML) nuclear
bodies. HIPK2 is activated by ultraviolet (UV) radiation and selectively
phosphorylates p53 at Ser 46, thus facilitating the CBP-mediated acetylation of
p53 at Lys 382, and promoting p53-dependent gene expression. Accordingly, the
kinase function of HIPK2 mediates the increased expression of p53 target genes,
which results in growth arrest and the enhancement of UV-induced apoptosis.
Interference with HIPK2 expression by antisense oligonucleotides impairs UVinduced apoptosis. Our results imply that HIPK2 is a novel regulator of p53
effector functions involved in cell growth, proliferation and apoptosis.
(Hofmann et al., 2002)
T55: phosphorylated by TAF1
The largest subunit of TFIID, TAF1, possesses an intrinsic protein kinase activity
and is important for cell G1 progression and apoptosis. Since p53 functions by
inducing cell G1 arrest and apoptosis, we investigated the link between TAF1
and p53. We found that TAF1 induces G1 progression in a p53-dependent
manner. TAF1 interacts with and phosphorylates p53 at Thr-55 in vivo.
Substitution of Thr-55 with an alanine residue (T55A) stabilizes p53 and impairs
the ability of TAF1 to induce G1 progression. Furthermore, both RNAi-mediated
TAF1 ablation and apigenin-mediated inhibition of the kinase activity of TAF1
markedly reduced Thr-55 phosphorylation. Thus, phosphorylation and the
resultant degradation of p53 provide a mechanism for regulation of the cell cycle
by TAF1. Significantly, the Thr-55 phosphorylation was reduced following DNA
damage, suggesting that this phosphorylation contributes to the stabilization of
p53 in response to DNA damage.
(Li et al., 2004)
94-312 (or 100-300): sequence-specific DNA-binding core domain
…six “hot spots” stand out as most frequently associated with human cancer
(R175H, G245S, R248Q, R249S, R273H, and R282W) (Joerger et al., 2004).
(O'Keefe et al., 2003) - fig 1A shows this domain as 100-300.
305-321: NLS (O'Keefe et al., 2003) - fig 1A
325-356: oligomerization domain
The crystal structure of the tetramerization domain of p53 (residues 325 to 356)
was determined at 1.7 angstrom.... The monomer, which consists of a beta
strand and an alpha helix, associates with a second monomer across an
antiparallel beta sheet and an antiparallel helix-helix interface to form a dimer.
Two of these dimers associate across a second and distinct parallel helix-helix
interface to form the tetramer. (Jeffrey et al., 1995)
The three-dimensional structure of the oligomerization domain (residues 319 to
360) of the tumor suppressor p53 has been solved by multidimensional
heteronuclear magnetic resonance (NMR) spectroscopy. The domain forms a 20kilodalton symmetric tetramer with a topology made up from a dimer of dimers.
The two primary dimers each comprise two antiparallel helices linked by an
antiparallel beta sheet. One beta strand and one helix are contributed from each
monomer. The interface between the two dimers forming the tetramer is
mediated solely by helix-helix contacts. The overall result is a symmetric, fourhelix bundle with adjacent helices oriented antiparallel to each other and with the
two antiparallel beta sheets located on opposing faces of the molecule. The
tetramer is stabilized not only by hydrophobic interactions within the protein core
but also by a number of electrostatic interactions. The implications of the
structure of the tetramer for the biological function of p53 are discussed. (Clore et
al., 1994)
We report the solution structure of the minimum transforming domain (residues
303-366) of human p53 (p53tet) determined by multidimensional NMR
spectroscopy. This domain contains a number of important functions associated
with p53 activity including transformation, oligomerization, nuclear localization
and a phosphorylation site for p34/cdc2 kinase. p53tet forms a symmetric dimer
of dimers that is significantly different from a recent structure reported for a
shorter construct of this domain. Phosphorylation of Ser 315 has only minor
structural consequences, as this region of the protein is unstructured. Modelling
based on the p53tet structure suggests possible modes of interaction between
adjacent domains in full-length p53 as well as modes of interaction with DNA.
(Lee et al., 1994)
339-346: minimal domain for transcriptional repression
We found only eight amino acids (339-346) of the COOH-terminal domain
(termed P53MRD) that possess activities of repression. The exact location of this
minimal domain is on the E6-binding region, and it lacks the ability of
tetramerization. P53MRD is able to repress the transcription of p53 while not
affecting VP16. The mutants (amino acids M340P and F341D) of native p53 also
lost transcriptional repression of the thymidine kinase chloramphenicol
acetyltransferase promoter. These results suggest that this eight-amino acid
element is required for the repression of p53.
(Hong et al., 2001)
340-350: NES (O'Keefe et al., 2003) - fig 1A
359-367: USP7-binding motif
The ubiquitin-specific protease, USP7, has key roles in the p53 pathway whereby
it stabilizes both p53 and MDM2. We show that the N-terminal domain of USP7
binds two closely spaced 4-residue sites in both p53 and MDM2, falling between
p53 residues 359-367 and MDM2 residues 147-159. Cocrystal structures with
USP7 were determined for both p53 peptides and for one MDM2 peptide. These
peptides bind the same surface of USP7 as Epstein-Barr nuclear antigen-1,
explaining the competitive nature of the interactions. The structures and
mutagenesis data indicate a preference for a P/AXXS motif in peptides that bind
USP7. Contacts made by serine are identical and crucial for all peptides, and
Trp165 in the peptide-binding pocket of USP7 is also crucial. These results help
to elucidate the mechanism of substrate recognition by USP7 and the regulation
of the p53 pathway. (Sheng et al., 2006)
363-393: regulatory domain (O'Keefe et al., 2003) - fig 1A
K370 methylation
Specific sites of lysine methylation on histones correlate with either activation or
repression of transcription. The tumour suppressor p53 is one of only a few nonhistone proteins known to be regulated by lysine methylation. Here we report a
lysine methyltransferase, Smyd2, that methylates a previously unidentified site,
Lys 370, in p53. This methylation site, in contrast to the known site Lys 372, is
repressing to p53-mediated transcriptional regulation. Smyd2 helps to maintain
low concentrations of promoter-associated p53. We show that reducing Smyd2
concentrations by short interfering RNA enhances p53-mediated apoptosis. We
find that Set9-mediated methylation of Lys 372 inhibits Smyd2-mediated
methylation of Lys 370, providing regulatory cross-talk between post-translational
modifications. In addition, we show that the inhibitory effect of Lys 372
methylation on Lys 370 methylation is caused, in part, by blocking the interaction
between p53 and Smyd2. Thus, similar to histones, p53 is subject to both
activating and repressing lysine methylation. Our results also predict that Smyd2
may function as a putative oncogene by methylating p53 and repressing its
tumour suppressive function.
(Huang et al., 2006)
K372 methylation
Here we report a novel mechanism of p53 regulation through lysine methylation
by Set9 methyltransferase. Set9 specifically methylates p53 at one residue within
the carboxyl-terminus regulatory region. Methylated p53 is restricted to the
nucleus and the modification positively affects its stability. Set9 regulates the
expression of p53 target genes in a manner dependent on the p53-methylation
site. The crystal structure of a ternary complex of Set9 with a p53 peptide and the
cofactor product S-adenosyl-l-homocysteine (AdoHcy) provides the molecular
basis for recognition of p53 by this lysine methyltransferase.
(Chuikov et al., 2004)
Recently, we discovered that lysine methylation of p53 at K372 by Set7/9 (also
known as SET7 and Set9) is important for transcriptional activation and
stabilization of p53. In this report we provide a molecular mechanism for the
effect of p53 methylation on transcription. We demonstrate that Set7/9 activity
toward p53, but not the nucleosomal histones, is modulated by DNA damage.
Significantly, we show that lysine methylation of p53 is important for its
subsequent acetylation, resulting in stabilization of the p53 protein. These p53
modification events can be observed on the promoter of p21 gene, a known
transcriptional target of p53. Finally, we show that methylation-acetylation
interplay in p53 augments acetylation of histone H4 in the promoter of p21 gene,
resulting in its subsequent transcriptional activation and, hence, cell cycle arrest.
Collectively, these results suggest that the cross talk between lysine methylation
and acetylation is critical for p53 activation in response to DNA damage and that
Set7/9 may play an important role in tumor suppression.
(Ivanov et al., 2007)
…we created a null allele of Set7/9 in mice. Cells from Set7/9 mutant mice fail to
methylate p53 K369, are unable to induce p53 downstream targets upon DNA
damage, and are predisposed to oncogenic transformation. Importantly, we find
that methylation of p53 by Set7/9 is required for the binding of the
acetyltransferase Tip60 to p53 and for the subsequent acetylation of p53. We
provide the first genetic evidence demonstrating that lysine methylation of p53 by
Set7/9 is important for p53 activation in vivo and suggest a mechanistic link
between methylation and acetylation of p53 through Tip60.
(Kurash et al., 2008)
Set7/9 recognizes and binds to the p53 motif: K370-S371-S372-K373.
(Couture et al., 2006) - fig 2a
K382: acetylation site
hSIR2(SIRT1) binds and deacetylates the p53 protein with a specificity for its Cterminal Lys382 residue, modification of which has been implicated in the
activation of p53 as a transcription factor. Expression of wild-type hSir2 in human
cells reduces the transcriptional activity of p53.
(Vaziri et al., 2001)
p53 ubiquitination by synoviolin/HRD1
Synoviolin, also called HRD1, is an E3 ubiquitin ligase and is implicated in
endoplasmic reticulum -associated degradation. In mammals, Synoviolin plays
crucial roles in various physiological and pathological processes, including
embryogenesis and the pathogenesis of arthropathy. However, little is known
about the molecular mechanisms of Synoviolin in these actions. To clarify these
issues, we analyzed the profile of protein expression in synoviolin-null cells.
Here, we report that Synoviolin targets tumor suppressor gene p53 for
ubiquitination. Synoviolin sequestrated and metabolized p53 in the cytoplasm
and negatively regulated its cellular level and biological functions, including
transcription, cell cycle regulation and apoptosis. Furthermore, these p53
regulatory functions of Synoviolin were irrelevant to other E3 ubiquitin ligases for
p53, such as MDM2, Pirh2 and Cop1, which form autoregulatory feedback loops.
Our results provide novel insights into p53 signaling mediated by Synoviolin.
(Yamasaki et al., 2007)
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