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ISSN: 2168-9857
Medical & Surgical Urology
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P53: The Wall Watcher

Nektarios Barabutis1* and John D. Catravas1,2

1Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, United States

2School of Medical Diagnostic and Translational Sciences, College of Health Sciences, Old Dominion University, Norfolk, Virginia, United States

*Corresponding Author:
Nektarios Barabutis
Frank Reidy Research Center for Bioelectrics
Old Dominion University, Norfolk, VA 23508, United States
Tel: 706- 294-9169
E-mail: [email protected]

Received date: October 12, 2015; Accepted date: October 13, 2015; Published date: October 18, 2015

Citation: Barabutis N, Catravas JD (2015) P53: “The Wall Watcher”. Med Surg Urol 4:e112. doi: 10.4172/2168-9857.1000e112

Copyright: © 2015 Barabutis N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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The “guardian of the genome” was introduced in 1979 when p53 was recognized as the cellular partner of SV-40 large T antigen [1]. A plethora of independent studies revealed that this 53kDa protein is a transcription factor mostly mutated in human cancers which dictates cellular fate by signaling cell cycle arrest, apoptosis or senescence [2]. The intense cross - talking between inflammation and carcinogenesis, lead several groups to explore the anti-inflammatory role of p53 in malignancies. This effort revealed that the tumor suppressor activity of that molecule is associated with the induction of multiple antiinflammatory responses both in cancerous and normal tissues [3]. The now well - established reciprocal negative regulation of p53 and NF-κB highlight the importance of p53 in the defense against inflammatory agents.

NF-κB-induced inflammatory cytokines reduce p53 transcriptional activity and agents that down regulate NF-κB cause p53 activation [4]. P53 is known to suppress the cyclooxygenase 2 gene and to antagonize pp60src-induced cell migration and proliferation in atherosclerosis [5,6]. P53 knockout mice are more susceptible to the LPS-induced acute lung injury, exhibit stronger responses to LPS stimulation, robust induction of pro-inflammatory cytokines and increased NF- κB DNA binding activity compared to the relevant wild type controls [7]. Mice with a p53 P72R mutation have an enhanced response to inflammatory challenges [8]. Bleomycin-induced pulmonary cell infiltration and disruption of alveolar architecture is increased in p53 null mice compared to wild type [9,10]. p53 null mice exposed to ionizing radiation exhibit a more rapid invasion of inflammatory cells and fibroblasts into the affected tissues than do wild type controls [11].

Hsp90 regulates the intracellular milieu by stabilizing and activating structural components, kinases and transcriptions factors which serve as important inflammatory mediators [12]. Although Hsp90 inhibitors were initially developed as antineoplastic drugs, an emerging body of evidence suggests that their anti-inflammatory activity enable them to have a beneficial role in the wider spectrum of human pathology [13- 15]. We recently remonstrate that p53 is an Hsp90 client protein and that the anti-inflammatory and vascular barrier protective effects of Hsp90 inhibitors are due-at least in part- to p53 mediated actions [16].

Endothelial barrier dysfunction is a cause and consequence of inflammatory responses and is involved in the development of Acute Lung Injury (ALI) and the Acute Respiratory Distress Syndrome (ARDS) [17]. The barrier integrity in endothelial cells is regulated by the small GTPases Rac1 and RhoA, which orchestrate the barrier protective and disruptive elements of the endothelium [18]. They cycle between an inactive GDP- and an active GTP-bound state. This cycle is regulated by GTPase activating proteins (GAP), which increase the intrinsic rate of GTP hydrolysis and guanine nucleotide exchange factors (GEF), which push the GTPases into a GTP-bound state [19]. Rac1 and RhoA exert opposing effects on barrier function by inducing different patterns of cytoskeletal and cellular contact remodeling [20]. These modifications lead to either endothelial barrier protection, by strengthening the integrity of its key components, or to endothelial barrier dysfunction by opening endothelial cell junctions and promoting the formation of intracellular gaps [21]. Conversely, activation of RhoA by inflammatory mediators, including LPS, activates ROCK1/2 which in turn induces the phosphorylation of myosin light chain kinase II [22]. These effects result in actomyosin contraction, actin stress fiber formation and barrier integrity disruption [23].

The robust p53-induced anti-inflammatory responses are partially mediated by the regulation of the Rho GTPases; namely the restriction of the Ras-induced RhoA stimulation and the resulting suppression of MLCII phosphorylation [24]. RhoA activity is enhanced in p53-/- cells. P53 negatively regulates the expression of RhoA, ROCK1 and ROCK2 [25]. The latter is exerted via transcriptional regulation of Notch1, which negatively regulates ROCK expression [26]. We have recently demonstrated both in vivo and in vitro that Hsp90 inhibitors stabilize p53 which in turn protects against LPS-induced endothelial barrier dysfunction by disrupting the RhoA/MLCII inflammatory pathway [16]. Thus, p53 appears to regulate endothelial cellular function by orchestrating protective responses towards the suppression of host-directed inflammation. Future studies will likely enlighten the expanding p53 universe by elucidating the exact role of the cellular Wall Watcher on the maintenance of the vascular integrity.

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