p53, p63 and p73 – solos,alliances and feuds among family members

p53 controls crucial stress responses that play a major role in preventing malignant transformation. Hence, inactivation of p53 is the single most common genetic defect in human cancer. With the recent discovery of two close structural homologs, p63 en p73, we are getting a broader view of a fascinating gene family that links developmental biology with tumor biology. While unique roles are apparent for each of these genes, intimate biochemical cross-talk among family members suggests a functional network that might influence many different aspects of individual gene action. The most interesting part of this family network derives from the fact that the p63 and p73 genes are based on the ‘two-genes-in-one’ idea, encoding both agonist and antagonist in the same open reading frame. In this review, we attempt to present an overview of the current status of this fast moving field.     

Biomagnification of p, p′-DDT and Methoxychlor by Bacteria

Aerobacter aerogenes and Bacillus subtilis accumulated p, p'-DDT and methoxychlor directly from water. Uptake of both (14)C-labeled organochlorine insecticides was rapid; 80 to 90% of the 24-h residues were reached within 30 min. Total cellular residues varied linearly with concentrations of DDT and methoxychlor in water ranging from 0.5 to 5.0 mug/liter. The residue magnification factors from water were between 1,400- to 4,300-fold, but were independent of insecticide concentrations in water. When the insecticide-exposed microbial cells were washed with pesticide-free water, DDT residues were 45% in A. aerogenes and 30% in B. subtilis, whereas the methoxychlor level decreased nearly 75% in both organisms. Subsequent washing did not further reduce the insecticide residue. Autoclave-killed bacteria also rapidly adsorbed DDT and methoxychlor from water and, in some instances, residues were higher than in the living cells. Molecular polarity and lipid solubility appear to influence the retention of the organochlorine insecticides by bacterial cells.     

巨噬细胞免疫调变信号:Raf-1,MAPK p44,MAPK p42和p38 MAPK的研究

为了了解巨噬细胞免疫调变机理,我们应用LPS和PMA处理小鼠抑制性巨噬细胞,观察到Ras下游信号分子Raf-1,分裂原激活蛋白激酶MAPK p44,MAPK p42和p38 MAPK均被活化,发现forskolin能增强p38 MAPK的活性,进一步提示PKC和PKA途径增强了p38 MAPK的磷酸化效应,为我们了解LPS如何激活p38 MAPK信号通路提供了一个新的机会。     

WITHDRAWN: Expression of p53, p63, and p73 isoforms in squamous cell carcinoma and adenocarcinoma of esophagus☆,☆☆

Diabetic microangiopathy is often observed in diabetic patients, but there is little evidence regarding the relationship between post-prandial glycemia or insulinemia and the incidence of diabetic microangiopathy. In this study, to elucidate the relationship between post-prandial glycemia (or insulinemia) and diabetic microangiopathy, we performed a cross-sectional study of 232 subjects with type 2 diabetes mellitus who were not being treated with insulin injections. A multiple regression analysis showed that post-prandial hyperglycemia independently correlated with the incidence of diabetic retinopathy and neuropathy. Post-prandial hyperglycemia also correlated, although not independently, with the incidence of diabetic nephropathy. In addition, interestingly, post-prandial hypoinsulinemia independently correlated with the incidence of diabetic retinopathy, although not correlated with diabetic neuropathy or nephropathy. In conclusion, post-prandial hyperglycemia, rather than fasting glycemia or hemoglobin A1c levels, is an important predictor of the incidence of diabetic microangiopathy in Japanese type 2 diabetic patients.     

p18^INK4C,p19^INK4D的结构,功能及细胞分化

ｐ１８＾ＩＮＫ４Ｃ和ｐ１９ＩＮＫ４Ｄ是细胞周期调控中的两种抑制因子,属于ＣＫＩｓ中的ＩＮＫ４家族蛋白,具有周期依赖性表达模式,特异性抑制Ｇ１ＣＤＫ４／６的激酶活性。同时也参与一些组织的终末分化过程,在细胞增殖周期与分化调控方法发挥偶联作用。     

Δ122p53, a mouse model of Δ133p53α, enhances the tumor-suppressor activities of an attenuated p53 mutant

Growing evidence suggests the Δ133p53α isoform may function as an oncogene. It is overexpressed in many tumors, stimulates pathways involved in tumor progression, and inhibits some activities of wild-type p53, including transactivation and apoptosis. We hypothesized that Δ133p53α would have an even more profound effect on p53 variants with weaker tumor-suppressor capability. We tested this using a mouse model heterozygous for a Δ133p53α-like isoform (Δ122p53) and a p53 mutant with weak tumor-suppressor function (mΔpro). The Δ122p53/mΔpro mice showed a unique survival curve with a wide range of survival times (92–495 days) which was much greater than mΔpro/- mice (range 120–250 days) and mice heterozygous for the Δ122p53 and p53 null alleles (Δ122p53/-, range 78–150 days), suggesting Δ122p53 increased the tumor-suppressor activity of mΔpro. Moreover, some of the mice that survived longest only developed benign tumors. In vitro analyses to investigate why some Δ122p53/mΔpro mice were protected from aggressive tumors revealed that Δ122p53 stabilized mΔpro and prolonged the response to DNA damage. Similar effects of Δ122p53 and Δ133p53α were observed on wild-type of full-length p53, but these did not result in improved biological responses. The data suggest that Δ122p53 (and Δ133p53α) could offer some protection against tumors by enhancing the p53 response to stress.The p53 tumor suppressor is most important for preventing cancers. p53 controls cell fate in response to stress by inducing apoptosis, cell cycle arrest/senescence, DNA repair (reviewed in Braithwaite et al.,^{1, 2} Oren,³ and Speidel⁴) or possibly restricting supply of basic substrates for metabolism.^{5, 6, 7} The regulation of p53 function has recently become more complex with the discovery of 13 isoforms, which may interfere with the normal functioning of full-length (FL) p53.^{8, 9, 10, 11, 12, 13, 14} An alternative promoter in intron 4 generates the Δ133p53 isoforms (Δ133p53α, and with additional alternative splicing in intron 9, Δ133p53β, and Δ133p53γ¹¹).The Δ133p53α isoform is expressed in many tissues, but elevated levels have been found in several cancers.^{11, 15, 16} Although the function(s) of Δ133p53α are not fully understood, growing evidence suggests it may have tumor-promoting capacities. Reducing Δ133p53α levels in the U87MG glioblastoma cell line reduced its ability to migrate and stimulate angiogenesis.¹⁷ Δ133p53α may also interfere with the tumor-suppressor functions of FLp53. The zebrafish ortholog of Δ133p53α, Δ113p53, inhibited p53-mediated apoptosis,¹⁸ and overexpression of Δ133p53α inhibited p53-directed G₁ cell cycle arrest.¹⁶Previously, we reported the construction and characterization of a mouse expressing an N-terminal truncation mutant of p53 (designated Δ122p53) that is very similar to Δ133p53α, providing the first mouse model of the Δ133p53α isoform.^{19, 20} Δ122p53 was found to increase cell proliferation and in p53 null cells transduced with a Δ122p53 expressing retrovirus, inhibited the transactivation of CDKN1a (encoding) p21^CIP1 and MDM2 by FLp53.^{19, 20} As well as elevating cell proliferation, homozygote Δ122p53 mice exhibited a profound pro-inflammatory phenotype, including increased serum interleukin-6 (IL-6) and γ-interferon (γ-IFN), and features of autoimmune disease.^{19, 20} The mice were tumor-prone displaying a complex tumor spectrum, but predominantly B-cell lymphomas and osteosarcomas. Thus, most evidence supports a role for the Δ133p53α isoform as a dominant oncogene that may interfere with normal FLp53 tumor-suppressor functions, but also has additional ''gain-of-function'' properties to promote tumor progression, probably through inflammatory mechanisms.²¹Given the above data, we reasoned that in an environment where p53 tumor-suppression capacity is compromised, such as in the context of the R72P allele^{22, 23, 24} or where p53 levels are reduced,^{25, 26, 27} the influence of Δ133p53α isoform on FLp53 function would be greater, leading to rapid tumor formation with a phenotype that would resemble that of the isoform alone. To test this, we generated mice heterozygous for Δ122p53 and a p53 mutant (mΔpro) that we previously described, that has attenuated tumor-suppressor activity.^{28, 29} The mΔpro mouse model is missing part of the p53 proline rich domain (PRD, amino acids 58–88). These mice are defective for DNA damage-induced apoptosis, and show a delayed and impaired cell cycle arrest response. Homozygous mΔpro mice develop late onset follicular B-cell tumors, while mΔpro heterozygotes developed few tumors in the presence of a wild-type p53 allele, or an early onset T-cell lymphoma in a p53-null background. In the latter case, the onset and tumor spectrum are indistinguishable from p53-null mice.²⁸In the current study, we found that, in contrast to our hypothesis, many Δ122p53/mΔpro mice showed extended survival compared with Δ122p53 homozygotes. In vitro analyses to explain this phenomenon suggested that Δ122p53 allele can enhance mΔpro tumor-suppressor functions, in particular cell cycle arrest.     

温阳化瘀法对月经周期紊乱患者p53,p21,MDM2蛋白表达的影响

目的:通过对月经周期紊乱患者的细胞周期相关基因的表达水平进行分析,得出温阳化瘀法在此病上的治疗效果。方法:选取我院妇科收治的月经周期紊乱患者120例,参照随机原则共分为2组,其中西医治疗组59例,给予醋酸甲羟孕酮片和克罗米芬口服;实验组61例,在西医治疗基础上给予温阳化瘀中药治疗,每日1剂;另外随机选取同期体检健康的60名女性作为正常对照组,在治疗结束后,应用免疫组化方法对全部受试者进行p53、p21以及MDM2蛋白表达检测,同时应用统计学软件对相关结果进行分析。结果:1p53和p21蛋白的阳性表达主要在细胞核,MDM2蛋白阳性表达定位在细胞核和(或)胞质;2正常子宫内膜组织中p53蛋白阳性表达率为(36.67%),p21表达率为(33.33%),显著高于月经周期紊乱患者,中药治疗组的p53蛋白阳性表达率为(19.67%),p21达率为(18.03%),显著高于西医治疗组,P0.05,差异有统计学意义;3正常子宫内膜组织中MDM2蛋白阳性表达率为(1.67%),显著低于月经周期紊乱患者,中药治疗组的MDM2蛋白阳性表达率为(32.77%),显著低于西医治疗组(50.85%),P0.05,差异有统计学意义。结论:与健康妇女相比,月经周期紊乱患者的p53和p21蛋白阳性表达率显著降低,MDM2蛋白阳性率显著升高,应用温阳化瘀法能够显著改善月经周期紊乱患者细胞周期相关基因的表达水平。     

绿茶对人胃癌细胞株中p21,p53蛋白表达的影响

应用免疫细胞化学方法检测ＳＧＣ—７９０１胃癌细胞株中ｐ２１、ｐ５３蛋白的表达,以探讨绿茶的抗癌作用机理。结果表明：绿茶提取物明显抑制ＳＧＣ—７９０１胃癌细胞株中ｐ２１ｒａｓ、ｐ５３蛋白的表达,并有剂量效应。提示绿茶对ｐ２１、ｐ５３基因突变可能有修复作用     

Exposure to p,p′-DDE: A Risk Factor for Type 2 Diabetes

Background

Persistent organic pollutants (POPs), such as PCBs, DDT and dioxins have in several cross-sectional studies shown strong associations with type 2 diabetes mellitus. Reversed causality can however not be excluded. The aim of this case-control study was to evaluate whether POPs concentration is a risk factor for type 2 diabetes.

Methodology/Principal Findings

A case-control study was performed within a well-defined cohort of women, age 50–59 years, from the Southern part of Sweden. Biomarkers for POP exposure, 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p′-DDE) were analyzed in stored serum samples, which were collected at the baseline examination when the cohort was established. For 107 out of the 371 cases, serum samples were stored at least three years before their type 2 diabetes was diagnosed. In this data set, CB-153 and p,p′-DDE were not associated with an increased risk to develop type 2 diabetes. However, when only the cases (n = 39) that were diagnosed more than six years after the baseline examination and their controls were studied, the women in the highest exposed quartile showed an increased risk to develop type 2 diabetes (OR of 1.6 [95% 0.61, 4.0] for CB-153 and 5.5 [95% CI 1.2, 25] for p,p′-DDE).

Conclusions/Significance

The results from the present case-control study, including a follow-up design, confirms that p,p′-DDE exposure can be a risk factor for type 2 diabetes.     

p,p′-Dichlorodiphenyldichloroethylene Induces Colorectal Adenocarcinoma Cell Proliferation through Oxidative Stress

p, p′-Dichlorodiphenyldichloroethylene (DDE), the major metabolite of Dichlorodiphenyltrichloroethane (DDT), is an organochlorine pollutant and associated with cancer progression. The present study investigated the possible effects of p,p′-DDE on colorectal cancer and the involved molecular mechanism. The results indicated that exposure to low concentrations of p,p′-DDE from 10⁻¹⁰ to 10⁻⁷ M for 96 h markedly enhanced proliferations of human colorectal adenocarcinoma cell lines. Moreover, p,p′-DDE exposure could activate Wnt/β-catenin and Hedgehog/Gli1 signaling cascades, and the expression level of c-Myc and cyclin D1 was significantly increased. Consistently, p,p′-DDE-induced cell proliferation along with upregulated c-Myc and cyclin D1 were impeded by β-catenin siRNA or Gli1 siRNA. In addition, p,p′-DDE was able to activate NADPH oxidase, generate reactive oxygen species (ROS) and reduce GSH content, superoxide dismutase (SOD) and calatase (CAT) activities. Treatment with antioxidants prevented p,p′-DDE-induced cell proliferation and signaling pathways of Wnt/β-catenin and Hedgehog/Gli1. These results indicated that p,p′-DDE promoted colorectal cancer cell proliferation through Wnt/β-catenin and Hedgehog/Gli1 signalings mediated by oxidative stress. The finding suggests an association between p,p′-DDE exposure and the risk of colorectal cancer progression.     

Efficient adult skeletal muscle regeneration in mice deficient in p38β, p38γ and p38δ MAP kinases

Adult skeletal muscle is a very stable tissue containing a small population of myofiber-associated quiescent satellite cells compared with late embryonic/neonatal skeletal muscle, which contains highly proliferating myoblasts and small actively growing myofibers, suggesting that specific regulatory pathways may control myogenesis at distinct developmental stages. The p38 MAPK signaling pathway is central for myogenesis, based on studies using immortalized and neonatal primary myoblasts in vitro. However, the contribution of this pathway to adult myogenesis has never been investigated. Four p38 isoforms (p38α, p38β, p38γ and p38δ) exist in mammalian cells, being p38α and p38γ the most abundantly expressed isoforms in adult skeletal muscle. Given the embryonic/neonatal lethality of p38α-deficient mice, here we investigate the relative contribution of p38β, p38γ and p38δ to adult myogenesis. Regeneration and myofiber growth of adult muscle proceeds with similar efficiency in mice lacking p38β, p38γ and p38δ as in wild-type control mice. In agreement with this, there is no difference in adult satellite cell behavior in vitro among the different genotypes. Importantly, the pattern of p38 activation (ascribed to p38α) remains unperturbed during satellite myogenesis in vitro and adult muscle regeneration in wild type and p38β-, p38γ- and p38δ-deficient mice, rendering p38α as the essential p38 isoform sustaining adult myogenesis. This study constitutes the first analysis addressing the functionality of p38β, p38γ and p38δ in satellite cell-dependent adult muscle regeneration and growth.     

一例原发闭经46,X,psu dic(X)(p22. 3::p22.3)

国外自1974年来,已有等臂双着丝粒X的多种病例报道^[5,6]。我国1982年才开始报道,至今已报道约有6例^[1-3]。现将我室发现一例报告如下。     

Five novel locations of Neocentromeres in human: 18q22.1, Xq27.1∼27.2, Acro p13, Acro p12, and heterochromatin of unknown origin

Since the first report in 1993, an ectopic centromere, i.e. neocentromere formation, has been reported in more than 100 small supernumerary marker chromosomes (sSMC), in 7 instances of centromere repositioning, and in about a dozen cases with more complex chromosomal rearrangements. Here we report 2 new cases with centromere repositioning and 3 neocentric sSMC consisting exclusively of heterochromatic material. Yet, no centromere formation was reported for the regions 18q22.1 and Xq27.1～27.2 as it was observed in the 2 cases with centromere repositioning here; in both cases, cytogenetically an inversion was suggested. Two of the 3 neocentric sSMC were derived from a short arm of an acrocentric chromosome. The remainder neocentric sSMC case was previously reported and was stainable only by material derived from itself.     

白介素—12p35,p40cDNA的克隆及在CHO上的表达

重组细胞因子的分子克隆及其表达对于我们了解免疫反应的分子基础和开发新的治疗药物有很重大的意义。例如：重组白介素一2能够引起人和实验肿瘤的退化[1],然而临床使用时常常伴有很大的毒性[1],提高细胞因子在临床使用效果的一种可能方法是细胞因子的联合用药。基于此种想法,研究者开始寻找能够减少白介素-2临床使用剂量并与其有协同作用的细胞因子。1990年stern等从NC－37细胞培养上清中分离出一种细胞因子,将其命名为白介素12［刁,该细胞因子是由40KD和35KD2个亚单位通过二硫键连接组成的异源Th聚体,下面详述白介素12的分子克隆…