Toward understanding the role of p53 in cardiovascular diseases

doi:10.4236/jbise.2013.62A025

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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

Email: [email protected], [email protected], [email protected], prash@bioclues.org

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-

OPEN ACCESS

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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