Purine analogues kill resting lymphocytes by p53-dependent and -independent mechanisms

To resolve the controversy concerning the role of p53 in the killing of resting lymphocytes by purine nucleoside analogues, we examined the cytotoxic effects of chlorodeoxyadenosine, fludarabine and deoxycoformycin (plus deoxyadenosine) on unstimulated spleen cells from p53-knockout versus wild-type mice. p53-knockout cells were more resistant to all three nucleosides than were wild-type cells. However, substantial killing still occurred in the absence of p53, indicating that purine analogues can kill resting lymphocytes by both p53-dependent and -independent mechanisms. We suggest that these results are relevant to chronic lymphoid malignancies, and that characterization of the p53-independent component of nucleoside action may indicate potential ways of overcoming therapeutic resistance.     

胃黏膜癌前病变中p53和增殖细胞核抗原的表达及其临床意义

目的探讨胃黏膜癌前病变中p53和增殖细胞核抗原（PCNA）的表达及其临床意义。方法顺序选择病理检查为肠上皮化生、不典型增生、肠上皮化生不典型增生共存的患者各20例（分别为A、B和C组）,另选20例正常者作为对照（D组）。免疫组化法检测其组织中p53和PCNA的表达。结果胃黏膜癌前病变中p53蛋白、PCNA表达水平均高于正常黏膜（P〈0．01）,表达水平从肠上皮化生、不典型增生到二者共存者呈递增趋势。结论p53和PCNA表达对评估胃黏膜癌前病变发展趋势有重要的临床价值,有助于早期发现胃癌。     

Loss of cryptochrome reduces cancer risk in p53 mutant mice

It is commonly thought that disruption of the circadian clock increases the cancer incidence in humans and mice. However, it was found that disruption of the clock by the Cryptochrome (Cry) mutation in mice did not increase cancer rate in the mutant mice even after exposing the animals to ionizing radiation. Therefore, in this study we tested the effect of the Cry mutation on carcinogenesis in a mouse strain prone to cancer because of a p53 mutation, with the expectation that clock disruption in this sensitized background would further increase cancer risk. Paradoxically, we find that the Cry mutation protects p53 mutant mice from the early onset of cancer and extends their median lifespan ≈50%, in part by sensitizing p53 mutant cells to apoptosis in response to genotoxic stress. These results suggest alternative therapeutic approaches in management of cancers associated with a p53 mutation.     

p53 Protein Expression and Its Relation to the Apoptotic Index in Prostate Adenocarcinoma

Background: Prostate cancer is one of the most commonly diagnosed cancers in males. Tumor suppressor gene p53 plays an important role in causing cell cycle arrest and allowing apoptosis to proceed. Objective: To investigate the expression of p53 protein and its relation to apoptosis and prostate cancer traditional prognostic indicators. Methods: In this study expression of p53 was examined in paraffin-embedded tissues from 50 cases of prostate carcinoma by immunohistochemistry and evaluated using an index of staining. Correlation between p53 expression and apoptosis was detected by TUNEL method. Pathological grade, Gleason score and stage of carcinoma were also determined. Results: P53 expression was observed in 48 of 50 cases (26-100% of tumor cells) with mean staining index of 141±65. A significant association between p53 expression and pathologic grade (r=0.37, p=0.004) and Gleason score (r= 0.4, p=0.009) of patients was observed. Apoptosis was detected in only 6 patients. p53 expression showed no correlation with apoptotic index. No correlation between p53 expression and stage or apoptosis and clinicopathological characteristics of patients was found. Conclusion: p53 expression showed a significant correlation with differentiation status of the prostate carcinoma and can be helpful as a prognostic marker. Decreased level of apoptosis observed in our cases was not correlated with p53 expression indicating the possible role of other regulatory molecules involved in the apoptosis.     

PKR,a p53 target gene,plays a crucial role in the tumor-suppressor function of p53

Type I IFN-induced expression of dsRNA-activated protein kinase (PKR) during viral infection is a well-established antiviral mechanism. However, little is known about the expression of PKR in the context of p53 and about PKR involvement in p53-mediated tumor suppression. Here, we report that PKR is a p53 target gene and plays an important role in the tumor-suppressor function of p53. Activation of p53 by genotoxic stress induces a significant level of PKR expression by acting on the newly identified cis-acting element (ISRE), which is separated from the IFN-stimulated responsive element on the PKR promoter, resulting in translational inhibition and cell apoptosis. The genotoxin-mediated inhibition of translation is associated with the p53/PKR/elF2a (eukaryotic initiation factor-2α) pathway. To some extent, p53 activation induced by DNA damage facilitates cell apoptosis by activating PKR. PKR-knockdown human colon cancer cells grew rapidly in nude mice and proved resistant to anti-cancer drugs. These data indicate that p53-mediated tumor suppression can be attributed at least in part to the biological functions of PKR induced by p53 in genotoxic conditions.     

Correlation of p53 gene mutation and expression of P53 protein in cholangiocarcinoma

AIM: To characterize the tumor suppressor gene p53 mutations and study the correlation of p53 gene mutation and the expression of P53 protein in cholangiocarcinoma. METHODS: A total of 36 unselected, frozen samples of cholangiocarcinoma were collected. p53 gene status(exon 5-8) and P53 protein were examined by automated sequencing and immunohistochemical staining, combined with the clinical parameters of patients. RESULTS: p53 gene mutations were found in 22 of 36 (61.1%) patients. Nineteen of 36 (52.8%) patients were positive for P53 protein expression. There were significant differences in extent of differentiation and invasion between the positive and negative expression of P53 protein. However, there were no significant differences in pathologic parameters between the mutations and non-mutations. CONCLUSION: The alterations of the p53 gene evaluated by DNA sequence analysis is relatively accurate. Expression of P53 protein could not act as an independent index to estimate the prognosis of cholangiocarcinoma.     

放大胃镜联合增殖细胞核抗原和p53对胃癌癌前病变的诊断价值

目的探讨放大胃镜、增殖细胞核抗原(PCNA)、p53在胃黏膜癌前病变中的诊断价值。方法应用放大胃镜对180例病人进行检查,放大胃镜下做出实时诊断,取活组织分别送病理学检查和免疫组化法检测PCNA和p53的表达。放大胃镜下胃小凹分为A、B、C、D、E5型[1]。结果放大胃镜下B～E4种胃小凹形态肠上皮化生发生率差异有统计学意义(χ2=16.24,P0.05),并且肠上皮化生的严重程度逐渐加重(相关系数=0.612,P0.05):C～E3种胃小凹形态与不典型增生的严重程度关系密切(χ2=11.31,相关系数=0.637,P0.05):B、C、D、E等4型胃小凹形态间PCNA和p53表达量差异有统计学意义(F=6.514,P0.05)。结论放大胃镜下胃黏膜微细结构形态可反映病变程度的轻重,PCNA和p53是重要的胃癌标志物,随访E型胃小凹、高PCNA和p53表达的患者有助于早期发现胃癌。     

肝细胞癌中p53基因突变的检测及新DNA片段的发现

目的：检测原代肝癌组织以及肝癌细胞系中ｐ５３的突变位点和频率,了解ｐ５３突变与肝癌发病和治疗的关系。方法：设计了３对引物,采用ＰＣＲ技术扩增ｐ５３的５－８外显子,然后进行ＤＮＡ测序鉴定,共测定了两个肝癌细胞系（ＢＥＬ－７４０２和２．２．１５）以及两例原代肝癌组织,其中５和６外显子用一对引物串联扩增出来,上游引物序列为５′－ＧＧＡＡＴＴＣＣＴＣＴＴＣＣＴＧＣＡＧ－３′,下游为：５′－ＧＧＡＡＴＴＣＡ     

p53与人类肺癌关系研究的进展

p53基因是目前人类所发现的与肿瘤发病相关性最大的抑癌基因(tumorsuppressorgene,TSG)。p53基因的点突变、缺失及灭活在肺癌的发生和进展过程中起着关键性的作用。随着各项研究的不断进展以及高新检测技术的出现,p53在肺癌的早期诊断中的价值得到进一步的肯定。同时,利用p53进行基因治疗及评价肺癌患者预后的研究也逐渐开展起来并取得一定成效。因此深入探讨p53基因与人类肺癌的关系具有重大的意义。本文就p53与人类肺癌关系研究的进展作一论述。     

p53 and Follow-up of Colorectal Adenocarcinomas

Circulating p53 antibodies (ELISA method), p53genetic alterations (SSCP), and protein overexpression(immunohistochemistry) were studied in 41 patients withcolorectal adenocarcinomas and 10 control patients. Carcinoembryonic antigen (CEA) and carbohydrateantigen 19.9 (CA 19-9) were evaluated in parallel. Tenpatients with p53 antibodies and p53 overexpression wereselected. Tumor DNA extracts from these 10 patients were analyzed by SSCP. Of all 41patients, 10 (24%) showed significant levels of p53antibodies, and p53 accumulation was detected in 20(48%) patients. In six patients, p53 antibodieconcentrations decreased rapidly after surgery; in twopatients, these levels returned to normal values. Of the10 selected tumors, eight revealed TP53 gene mutations.Only two patients with high values of both CEA and CA 19-9 developed p53 antibodies. Inconclusion, beside classical tumor markers, circulatingp53 antibodies may be considered as additional markersfor the management of patients with colorectaladenocarcinomas.     

幽门螺杆菌感染与胃粘膜上皮细胞凋亡、增殖及p53基因表达探讨

目的:研究幽门螺杆菌(Helieobacter pylori,HP)感染后胃粘膜组织p53基因表达改变和细胞凋亡及增殖的变化。方法:采用脱氧核糖核酸末端转移酶介导的缺口末端标记(TUNEL)技术及免疫组织化学方法对HP阳性者根除前后及HP阴性者的胃粘膜上皮组织中的细胞凋亡、增殖及p53蛋白表达状态进行原位观察和比较。结果:慢性活动性胃炎HP感染者细胞凋亡指数和增殖指数显著高于不伴HP感染者(P<0.01),根除前后比较差异亦显著(P<0.01)。HP阳性组突变型p53阳性率显著高于HP阴性组(P<0.05)。在HP相关性胃炎中,p53阳性者的细胞增殖指数显著高于p53阴性者(P<0.05)。结论:HP可引起胃粘膜上皮细胞凋亡和增殖改变,突变型p53异常表达可能参与此过程。说明HP与胃癌发生动态过程有关系。     

p53 gene mutations in soft-tissue sarcomas-correlations with p53 immunohistochemistry and DNA ploidy

The significance ofp53 mutations in a group of 67 soft-tissue tumors was examined using single-strand conformation polymorphism and direct sequencing analysis. Molecular findings were correlated with immunohistochemical detection of thep53 protein and DNA ploidy status. Mutations of thep53 gene were detected in 13 (19.5%) out of 67 cases of soft-tissue tumors. Only there were localized outside the conservative regions of thep53 gene. Six mutations were described for the first time in these tumors. Most of the mutations were point mutations in exons 5–8 and, in one case, a deletion at the 3-splice site of exon 5 could be demonstrated. There was no significant correlation between the occurrence ofp53 mutations and the histological grade, although a high number of mutations were defined in poorly differentiated tumors (grade 3). Molecular finding of ap53 gene mutation and immunohistochemical detection ofp53 expression did not correlate, which may be due to the high percentage of nonsense mutations in our study (50%). We confirm that only DNA sequencing allows a unique identification and differentiation of mutations in thep53 gene. Other factors may be responsible for the detection ofp53 protein in many cases. Histological grade correlated with aneuploidy. The frequency of mutations observed was in accordance with values quoted in the literature. Generally,p53 mutations andp53 overexpression are more likely to represent a late event in the oncogenesis of soft-tissue tumors.