J. Biomedical Science and Engineering, 2013, 6, 209-212 JBiSE
http://dx.doi.org/10.4236/jbise.2013.62A025 Published Online February 2013 (http://www.scirp.org/journal/jbise/)
Toward understanding the role of p53 in cardiovascular
diseases
Mohanalatha Chandrasekharan1, Silvia Vasquez2, Rajesh Kumar Galimudi3, Prashanth Suravajhala1
1Bioclues.org, IKP Knowledge Park, Secunderabad, India
2Instituto Peruano de Energía Nuclear, Centro Nuclear RACSO, Lima, Perú
3Department of Genetics, Osmania University, Hyderabad, India
Received 14 November 2012; revised 15 December 2012; accepted 22 December 2012
ABSTRACT
Tumour suppressor protein 53 (TP53 or simply p53)
is a well known protein linked to apoptosis, cell sig-
nalling, cascading and several myriad functions in
cells. Many diseases are linked to p53 though analysis
show only 216 interaction partners. Whether p53
plays an important role in cardiovascular diseases
(CVD) remains uncertain. Through this bioinfor-
matical analysis, we propose that p53 might play a
major role in CVD whilst being linked to Hypoxia
and Lupus. There could be evidence by pull down
assay studies. Whether its interactants play a role in
CVD remains to be studied using experiments, t houg h
the interaction maps show possible affect on other
diseases.
Keywords: TP53; Cardiovascular Disease;
Protein-Protein Interactions
1. INTRODUCTION
Tumour suppressor protein 53 (TP53 or simply p53) is
the common-most gene linked to various diseases. Lo-
cated on the human chromosome 17(17p13.1), it har-
bours four domains which play a crucial role in apoptosis
[1,2]. Recent association and interaction studies of p53
with various diseased proteins have caught interest to
researchers [3]. Cardiovascular disease (CVD) is one of
the most prevalent diseases worldwide and so there is
immense interest in chronic, mitochondrial and aging-
related conditions. For example, proteins, viz. sirtuin
(SIRT) family of NAD(+)-dependent deacetylases have
recently been known to be emerging as exciting targets
for CVD which regulates a variety of enzymes, metabo-
lites, transcription factors, co regulators, and enzymes
that regulate several tissues [4]. If in disorder, they result
in myocardial dysfunction through the deacetylation of
p53. Upregulated p53 induces the transition of cardiac
hypertrophy to heart failure through the suppression of
hypoxia inducible factor-1 (HIF-1), which regulates an-
giogenesis in the hypertrophied heart. In addition, as p53
is known to promote apoptosis, which in turn is involved
in heart failure, p53 might be a key molecule in trigger-
ing the development of heart failure from multiple me-
chanisms [5,6]. While p53 can modulate the activity and
expression of some other proteins have been recently
studied, whether or not there are potentially beneficial
effects remains to be understood. The actions of the ag-
ing proteins on the CVD have been well studied [7] with
important insights into the molecular circuitry of cardio-
vascular system which raises the prospect that p53 and
its cellular pathways contribute to disease pathogenesis.
However, proteins which are forcedly expressed induc-
ing apoptosis and their interaction partners have not been
studied and our current study is delved upon understand-
ing those protein interacting partners in treatment of such
candidates [8]. During hypoxia, p53 is accumulated and
interacts with an approximate 28 specific genes to nega-
tively regulate. It is then phosphorylated at Ser15 which
by virtue of ataxia telangiectasia-mutated pathways
(ATM) and both Ser15 and Thr18 get activated by CK-1.
While the protein binds to IκBβ and mSin 3A making
hypoxia levels less than 5% O2, it later enters to the nu-
cleus as a complex with mSin3A binding to the MDM2
gene. In the cytoplasm, MDM2 interacts with p53 via
AKT and HIF pathways. As HIF proteins family is a
regulator of O2 homeostasis, it is known that AKT path-
ways inhibits p53-mediated transcription and apoptosis.
2. METHODS
Through this study, we exploited the protein interaction
partners by showing evidence of DNA damage, activa-
tion of damage repair pathways, p53 expression and
apoptosis, involving a variety of different cell types with
respect to CVD. Genemania [9] and Genecards [10] were
searched for p53 and its interactants in relation to Car-

M. Chandrasekharan et al. / J. Biomedical Science and Engineering 6 (2013) 209-212 210
diomyopathy, Lupus, Hypoxia and Apoptosis. Genema-
nia analysis recognized 100 closely interacting p53 genes
in Homo sapiens of which 11 genes are involved in Hy-
poxia and 19 in Apoptosis including p53. Genecards
analysis identified a total of 1210 genes involved in Lu-
pus and 663 in Cardiomyopathy including p53. The re-
sult obtained from Genecards was carefully analysed to
restrict the study to p53 and its interactants. Thus the
investigation narrowed down to 15 genes for Lupus and
4 for Myopia. As few of these genes show their presence
in more than one of the four disorders of our interest,
combining the results we had 35 short listed candidates
(Please see Table 1) from our first set of analysis. Next
we subjected P53 to Osprey visualization [11] and it re-
turned 216 interacting partners (Figure 1). The outcome
was compared with the previous analysis and of the 35
genes, 10 (shown by bigger nodes in Figure 2) could be
mapped in common. The 35 short listed proteins have
been carefully segregated and annotated for subcellular
location and their coexistence for mapping these proteins
across the diseases [12]. TargetP [13,14] and Wolf-
PSORT [15] were supplemented for Homologene map-
ping and Subcellular location prediction and a consensus
was reached between them. Subcellular location predic-
tion was used to check the two proteins, if interacting
would lie in the same organelle (Please see Table 2).
Table 1. Homologene mapping and p53 as a root reference to proteins interactions.
Gene Hypoxia (H) Apoptosis (A)Lupus (L) Cardiomyopathy (C)
TP53 H A L C
PML, EP300, PMAIP1, BBC3, SIRT1 H A
MDM2 H L
TP63, CASP2 A C
MSH2, IFI16, BCL2L1 A L
MDM4, AQP1, CREBBP, USF1 H
AIFM2, PERP, SIVA1, TP53I3, TP73, HIC1, MYBBP1A,
DHCR24 A
HMGN2, NFKBIA, MBD4, APCS, HIC2, HSPA1A, S100B,
PTGS1, MKI67, TYMS L
HMGB1 C
Table 2. Subcellular location prediction for Homologenes using TargetP and WolfPSORT.
Gene TargetP WolfPSORT Consensus
TP53 N(1) N N
PML, EP300, PMAIP1,BBC3, SIRT1 N N N
MDM2 N N N
TP63, CASP2 N N N
MSH2 MitochondriaPlasma Membrane Mitochondria
IFI16, BCL2L1 N N N
MDM4, AQP1, CREBBP, USF1 N N N
AIFM2, PERP, SIVA1, TP53I3, TP73, HIC1, MYBBP1A,DHCR24 N N N
HMGN2, NFKBIA, MBD4, APCS, HIC2, HSPA1A, S100B, PTGS1, MKI67, TYMS N N N
HMGB1 N N N
N = Nucleus

M. Chandrasekharan et al. / J. Biomedical Science and Engineering 6 (2013) 209-212 211
Figure 1. Pipeline showing the annotation strategy in deci-
phering the knowledge specific to cardiovascular system of P53
and its interactants obtained from osprey evaluation.
3. RESULTS AND DISCUSSION
Of all the 216 possible protein interactors using osprey,
10 genes were chosen for further study. The p53 any-
ways plays a part in all four disorders but whether or not
suppression of this protein with respect to a specific dis-
ease cause a phenomenal change is not yet understood.
Only to understand this, we mapped the 35 short listed
proteins (Table 1 ) on to Osprey and from our annotation
we suggest 10 of them (marked by bigger nodes) are
putative candidates for the diseases. Furthermore sub-
cellular location confirms their possible role in the car-
diovascular system. We also found that MSH2 is found
both in mitochondria and cytoplasm suggesting that the
interacting partners of these proteins might also be
known in both organelles. Nevertheless, the role of
MSH2 in cardiovascular system cannot be turned away
as DNA repair system may also be present in CVD.
4. CONCLUSION
It is interesting to explore the role of p53 in cardiovascu-
lar diseases. Our approach, we believe has narrowed
down the experimentation in finding better candidates of
p53 in cardiovascular system. While MSH2 is known to
be found in both mitochondria and cytoplasm (or nu-
cleus), the subcellular location studies we have employed
has given a validation that MSH2 might also play an
Figure 2. Putative Protein Interaction Network (PIN) of p53.

M. Chandrasekharan et al. / J. Biomedical Science and Engineering 6 (2013) 209-212 212
important role in validating the role of these proteins
linked to p53, towards CVD. We believe and envisage
that the other proteins (highlighted as bold and bigger
nodes) are better candidates and it would be interesting
to run pull down assays for these proteins to check for
their candidacy in CVD.
5. ACKNOWLEDGEMENTS
We thank Dr. Tiratha Raj Singh for providing kind inputs.
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