Disease relevance of Tp53

• Experiments in LNCaP prostate cancer cells reveal that AR inhibits p53 protein accumulation in the nucleus, providing a post-transcriptional mechanism by which androgens control prostate cell growth and survival [1].
• The oncoprotein E1a induced p53-independent apoptosis in anoxic cells, which when suppressed by Bcl-2 permitted proliferation despite anoxia [2].
• Here, we show that a p53 protein, exhibiting two point mutations in its cDNA, is abundantly expressed in the AS-30D hepatoma [3].
• The p53 tumor suppressor protein inhibits tumor formation, in part by inducing apoptosis, which is inhibited by anti-apoptotic Bcl-2 family members Bcl-2 and adenovirus E1B 19K [4].
• The resultant data suggest that p38 MAPK mediated the CAPE-induced p53-dependent apoptosis in C6 glioma cells [5].

Psychiatry related information on Tp53

• The present results provide additional support for the view that NF-kappaB activation contributes to c-Myc and p53 induction and subsequent apoptosis in an excitotoxic model of Huntington's disease [6].
• As up-regulation of p53 has been described as a common feature of several neurodegenerative disorders, including Alzheimer's disease, 2 and novel analogues (3-16) were synthesized to (i) assess the value of tetrahydrobenzothiazole analogues as neuroprotective agents and (ii) define the structural requirements for p53 inactivation [7].

High impact information on Tp53

• The cells maintain high telomerase activity and p53- and Rb-dependent cell cycle checkpoint responses, and serum or genotoxic drugs induce them to acquire a senescence-like phenotype [8].
• Baby rat kidney (BRK) cell lines transformed by E1A and a temperature-sensitive p53 [tsp53(val135)] undergo rapid apoptosis when p53 assumes the wild-type conformation at the permissive temperature [9].
• In addition, there may exist at least two different mechanisms by which p53 can suppress cell-cycle progression, only one of which is dependent on p53-mediated transcription [9].
• Primary rat embryo fibroblasts were transformed by a p53 mutant (alanine to valine change at amino acid 135) plus ras [10].
• The S-phase cells appear to be immune to the p53 negative regulation of growth until they enter the next G1 period.(ABSTRACT TRUNCATED AT 250 WORDS)[10]

Chemical compound and disease context of Tp53

• Docosahexaenoic acid in combination with celecoxib modulates HSP70 and p53 proteins in prostate cancer cells [11].
• Involvement of tumor suppressor protein p53 and p38 MAPK in caffeic acid phenethyl ester-induced apoptosis of C6 glioma cells [5].
• The p53-upregulated modulator of apoptosis (Puma), a BH3-only member of the Bcl-2 protein family, is required for p53-dependent and -independent forms of apoptosis and has been implicated in the pathomechanism of several diseases, including cancer, acquired immunodeficiency syndrome, and ischemic brain disease [12].
• To determine whether enzymatic p53 glycosylation leads to angiotensin II formation followed by p53 phosphorylation, prolonged activation of the renin-angiotensin system, and apoptosis, ventricular myocytes were exposed to levels of glucose mimicking diabetic hyperglycemia [13].
• Apoptotic cell killing by hygromycin B did not require expression of wild-type p53 and was suppressed by both Bcl-2 and the Adenovirus type 5 E1B 19-kDa protein [14].

Biological context of Tp53

• Tp53-associated growth arrest and DNA damage repair gene expression is attenuated in mammary epithelial cells of rats fed whey proteins [15].
• However, it remains unknown whether these apoptotic proteases are generally involved in apoptosis triggered by other stimuli such as Myc and p53 [16].
• Neuronal cell apoptosis has been reported to require p53, whereas other data suggest that neuronal cell death may be independent of p53 [17].
• In summary these data provide a comprehensive view of the earliest events in AR-mediated prostate cell proliferation in vivo, and suggest that nuclear exclusion of p53 is a critical step in prostate growth [1].
• In conclusion, these results demonstrate that UDCA inhibits E2F-1 transcriptional activation of hepatocyte apoptosis, thus modulating p53 stabilization, NF-kappaB degradation, and expression of Bcl-2 family members [18].

Anatomical context of Tp53

• Ursodeoxycholic acid modulates E2F-1 and p53 expression through a caspase-independent mechanism in transforming growth factor beta1-induced apoptosis of rat hepatocytes [18].
• Nerve growth factor withdrawal-mediated apoptosis in naive and differentiated PC12 cells through p53/caspase-3-dependent and -independent pathways [17].
• Nitric oxide and superoxide induced p53 and Bax accumulation during mesangial cell apoptosis [19].
• This study was designed to elucidate the molecular events that lead to p53 stabilization, to examine the pathways involved in Dox-induced apoptosis, and to evaluate the effectiveness of pifithrin-alpha (PFT-alpha), a p53 inhibitor, in blocking apoptosis of rat H9c2 myoblasts [20].
• Among the mitochondria-dependent genes, p53 closely correlates with granulosa cell apoptosis during follicular development [21].

Associations of Tp53 with chemical compounds

• The provision of guanosine inhibited the increase in p53 [22].
• Early during cisplatin treatment, p53 was phosphorylated and upregulated [23].
• In contrast, cytokines in combination with pyrrolidine dithiocarbamate, which blocks endogenous superoxide dismutase, allowed p53 and Bax accumulation as well as DNA fragmentation [19].
• To study p53 and Bax protein accumulation in NO. and/or O2(-)-induced apoptosis, we used the NO-donor S-nitrosoglutathione (GSNO) and the redox cycler 2,3-dimethoxy-1,4-naphtoquione (DMNQ) [19].
• Modulation of nuclear steroid receptors by ursodeoxycholic acid inhibits TGF-beta1-induced E2F-1/p53-mediated apoptosis of rat hepatocytes [24].

Physical interactions of Tp53

• More importantly, p38 kinase formed a complex with p53 after the treatment of CAPE for 0.5 hr [5].
• The addition of exogenous ubiquitin to p53-Mdm2 complexes from apoptotic neurons restored p53 degradation [25].
• These results suggest a prominent role of JNK and p38, as well as their downstream AP-1 binding activation and p53 phosphorylation in mediating glutamate excitotoxicity [26].

Enzymatic interactions of Tp53

• On collagen plates, mechanical stress rapidly activated p38 MAPK that phosphorylated p53 in smooth muscle cells [27].

Regulatory relationships of Tp53

• Phospholipase D elevates the level of MDM2 and suppresses DNA damage-induced increases in p53 [28].
• Although this could represent a response to aberrant cell cycle progression, we show that only E2F1 induces apoptosis and that this coincides with an ability of E2F1 to induce accumulation of p53 protein [29].
• Parallel pathways of caspase-mediated apoptosis are activated later in the absence of functional p53 [17].
• Bcl-2 expression abolished cisplatin-induced apoptosis without blocking p53 phosphorylation or induction [23].
• Insulin-like growth factor-1 induces Mdm2 and down-regulates p53, attenuating the myocyte renin-angiotensin system and stretch-mediated apoptosis [30].

Other interactions of Tp53

• These data provide evidence that survival signals generated by PLD involve suppression of the p53 response pathway [28].
• These data suggest a role of dysregulation of Bcl-2 family genes and, at least in atypical lesions, of p53 overexpression, in basal and AMPH-induced apoptosis in nodules and HCCs [31].
• In this study we examined the role of p53 in the induction of apoptosis by TGF-beta1, and identified additional antiapoptosis targets for UDCA [18].
• Thus, the stimulation of different p53 targets could be instrumental in determining the outcome of CXCR 4 activation on neuronal survival in neuro-inflammatory disorders [32].
• A role for c-Jun N-terminal kinase 1 (JNK1), but not JNK2, in the beta-amyloid-mediated stabilization of protein p53 and induction of the apoptotic cascade in cultured cortical neurons [33].

Analytical, diagnostic and therapeutic context of Tp53

• Survival assays with XTT (sodium 3'-1-(phenylaminocarbonyl)-3,4-tetrazolium-bis(4-methoxy-6-nitro)benzene sulfonic acid) and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) demonstrated that lack of p53 is initially protective against apoptosis [17].
• Furthermore, Western blot analyses and double-immunofluorescent staining showed activation of c-Jun N-terminal kinase (JNK) and p53, and a localization of p53 in the dopaminergic neurons in the SN after thrombin, respectively [34].
• Although we did not find a difference in the inhibitor of DNA binding/differentiation-2 (Id2) and c-Myc protein contents between the denervated and control muscles, the protein content of tumour suppressor p53 was significantly increased in both the nuclear and the cytosolic fractions with denervation [35].
• These results suggested that arsenite induced apoptosis in the hepatocytes in vivo, through the enhancement of the activation of JNK and p38 MAPK caused by partial hepatectomy and the p53-dependent p21(WAF1/CIP1) protein expression [36].
• To facilitate study of its role in carcinogenesis using a common animal model, we determined the structure of the rat p53 gene [37].

References