Cellular and molecular mechanisms of development of the external genitalia

The limb and external genitalia are appendages of the body wall. Development of these structures differs fundamentally in that masculine development of the external genitalia is androgen dependent, whereas development of the limb is not. Despite this fundamental difference in developmental regulation, epithelial-mesenchymal interactions play key roles in the development of both structures, and similar regulatory molecules are utilized as mediators of morphogenetic cell-cell interactions during development of both the limb and external genitalia. Given the relatively high incidence of hypospadias, a malformation of penile development, it is appropriate and timely to review the morphological, endocrine, and molecular mechanisms of development of the genital tubercle (GT), the precursor of the penis in males and the clitoris in females. Morphological observations comparing development of the GT in humans and mouse emphasize the validity of the mouse as an animal model of GT development and validate the results of experimental studies. Accordingly, the use of mutant mice provides important insights into the roles of specific regulatory molecules in development of the external genitalia. While our current understanding of the morphological and molecular mechanisms of mammalian external genitalia development is still rudimentary, this review summarizes the current state of our knowledge and whenever possible draws from the rich experimental embryology literature on other relevant organs such as the developing limb. Future research on the hormonal and molecular mechanisms of GT development may yield strategies to prevent or reduce the incidence of hypospadias and to elucidate the molecular genetic mechanisms of GT morphogenesis, especially in relation to common organogenetic pathways utilized in other organ systems.     

p63基因的结构与功能

p63基因是肿瘤抑制基因p53家族成员之一,与p53基因表现出高度同源性.较之p53基因,p63基因更为复杂.p63的两个不同启动子和多种内含子剪接方式,导致p63基因编码产生多种亚型P63蛋白.这些P63亚型蛋白,在不同的组织不同的发育阶段发挥不同的生物学功能.本文就p63基因结构、p63在细胞周期和凋亡中的作用,以及在表皮发育中的功能等方面的研究进展作一概述.     

p63与p21在鼻咽癌细胞中的表达及相互作用的初步研究

鼻咽癌是中国南方地区常见的恶性肿瘤,p63是新发现的p53家族成员.本研究利用免疫组化方法对p63、p53及p21基因在鼻咽癌中的表达进行了检测,发现三者在鼻咽癌中均有表达;并利用染色质免疫共沉淀(ChIP)的方法对p63及p21的相互作用进行了初步研究,发现P63蛋白能与p21基因启动子区域的一个位点结合.     

Differential effects of p63 mutants on transactivation of p53 and/or p63 responsive genes

p63, known to play a role in development, has more recently also been implicated in cancer progression. Mutations in p63 have been shown to be responsible for several human developmental diseases. Differential splicing of the p63 gene gives rise to p63 isoforms, which can act either as tumor suppressors or as oncogene. In this report, we studied the effects of naturally occurring TAp637 mutants on the regulation of p53/p63 and p63 specific target genes. We observed significant differences among p63 mutants to regulate the p53/p63 and p63 specific target genes. Additionally, we observed a differential effect of p63 mutants on wildtype-p63-mediated induction ofp53/p63 and p63 specific target genes. We also demonstrated that these mutants differentially regulate the binding of wildtype p63 to the promoter of target genes. Furthermore, the effects of these mutants on cell death and survival were consistent with their ability to regulate the downstream targets when compared to wildtype TAp63T. In summary, our data demonstrate that p63 mutants exhibit differential effects on p63 and p53/p63 specific target genes and on the induction of apoptosis, and provide further insight into the function of p63.     

p63 and p73 expression in extrahepatic bile duct carcinoma and their clinical significance

p53 plays a pivotal role in the prevention of human tumor formation. p73 and p63 are new members of the p53 tumor suppressor family, which are becoming increasingly recognized as important players in human tumorigenesis. However, the roles of these proteins are not well elucidated in extrahepatic bile duct (EBD) carcinoma. We examined expressions of the p63 and p73 genes and proteins in normal biliary epithelia, biliary dysplasias, and EBD carcinomas using immunohistochemistry and RT-PCR analysis. p63 and p73 proteins were overexpressed in 26.3 and 41.0% of EBD carcinomas, respectively. p63 protein expression was more frequent in tumors with vascular invasion (P = 0.002) and distal location (P = 0.04), while p73 expression was more common in cancers with deeper tumor invasion (P = 0.04). Patients with tumors co-expressing both p63 and p73 were found to have a significantly worse overall survival rate compared to those with either p63 or p73 expression (P < 0.05) as determined in univariate and multivariate analyses. Our results strongly imply that the p53 family members have different functions in EBD carcinomas. Our data also indicate that interactions between p63 and p73 play an important role in tumorigenesis of EBD carcinoma.     

p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53

p53 mutations, occurring in two-thirds of all human cancers, confer a gain of function phenotype, including the ability to form metastasis, the determining feature in the prognosis of most human cancer. This effect seems mediated at least partially by its ability to physically interact with p63, thus affecting a cell invasion pathway, and accordingly, p63 is deregulated in human cancers. In addition, p63, as an 'epithelial organizer', directly impinges on epidermal mesenchimal transition, stemness, senescence, cell death and cell cycle arrest, all determinant in cancer, and thus p63 affects chemosensitivity and chemoresistance. This demonstrates an important role for p63 in cancer development and its progression, and the aim of this review is to set this new evidence that links p63 to metastasis within the context of the long conserved other functions of p63.     

肺癌组织中PCNA、p63和p53蛋白的表达及临床意义

目的:检测蛋白增殖细胞核抗原(PCNA)、p63和p53在肺癌组织中的表达情况,以探讨三者在肺癌的发生、发展中的生物学作用和临床意义。方法:选取195例肺癌组织(其中57例有癌旁组织),应用组织芯片技术和免疫组织化学方法观察三种蛋白的表达情况,并研究三者之间及其与临床病理参数的关系。结果:PCNA、p63和p53蛋白在肺癌组织中的阳性表达率分别为96.41%、38.46%及58.46%,但三者在癌旁组织中均无表达,差异有统计学意义(均P0.05);在肺癌组织中,PCNA、p63和p53蛋白的表达情况均与组织分型有关(P0.05),且PCNA、p53蛋白表达与分化程度有关(P0.05),分化越差,表达越高;p53表达与PCNA表达呈正相关(r=0.352,P=0.043),p63与p53、PCNA的表达不相关(P0.05)。结论:肺癌组织中PCNA、p63和p53蛋白的表达升高,三者均在肺癌的发生、发展中发挥着重要作用,并且临床可通过检测三者的蛋白水平,作为鉴别肺鳞状细胞癌与其他类型癌的重要参考指标,为病理诊断提供依据。     

小腹茧蜂亚科的雄外生殖器及族级单元系统发育的研究

对分布在东洋区和古北区的小腹茧蜂亚科 (膜翅目: 茧蜂科)21个属的67个种及外群折脉茧蜂属 (膜翅目: 茧蜂科) 2个种的雄外生殖器的5个性状进行了比较研究。在形态学研究的基础上,通过选用头部、胸部和腹部(包括雌雄外生殖器的性状) 等34个性状,运用支序分析的方法探讨了分布在东洋区和古北区的小腹茧蜂亚科21个属以及它们所属的族间的系统发育关系,并对Mason (1981) 的分类系统进行了重新评价。雄外生殖器和支序分析基本上证实并恢复了由Mason (1981) 确定的2个主要分支,即绒茧蜂族Apantelini+小腹茧蜂族Microgastrini和拱茧蜂族Fornicini+盘绒茧蜂族Cotesiini+侧沟茧蜂族MicroplitinI。绒茧蜂族Apantelini、拱茧蜂族Fornicini和侧沟茧蜂族Microplitini为单系群也被支持,但小腹茧蜂族Microgastrini和盘绒茧蜂族Cotesiini是否为单系群尚难于在树形图中体现,而且族内各属间的分支关系有变动。因此,尽管Mason的族级分类单元有一些欠缺,但仍是可信、实用的,不同意Walker等 (1990) 认为不应再使用Mason分族系统的观点。     

The role of p53 in treatment responses of lung cancer

Resistance to radio- and chemotherapy is a major problem in treatment responses of lung cancer. In this disease, biological markers, that can be predictive of response to treatment for guiding clinical practice, still need to be validated. Radiotherapy and most chemotherapeutic agents directly target DNA and in response to such therapies, p53 functions as a coordinator of the DNA repair process, cell cycle arrest, and apoptosis. In fact, it participates in the main DNA repair systems operative in cells, including NHEJ, HRR, NER, BER, and MMR. Given the high p53 mutation frequency in lung cancer which likely impairs some of the p53-mediated functions, a role of p53 as a predictive marker for treatment responses has been suggested. In this review, we summarize the conflicting results coming from preclinical and clinical studies on the role of p53 as a predictive marker of responses to chemotherapy or radiotherapy in lung cancer.     

p63 in prostate biology and pathology

The identification of stem cells and differentiation programs regulating the development and maintenance of the normal prostate epithelium is essential for the identification of the cell type(s) and molecular alterations involved in the development and propagation of prostate cancer (CaP). The p53-homologue p63 is highly expressed in normal prostate basal cells and is a clinically useful biomarker for the diagnosis of CaP. Importantly, p63 has been shown to play a critical role in prostate development. Recent experimental evidence also suggests that this gene is essential for normal stem cell function in the prostate as well as other epithelial organs. Future studies aimed at better defining the role of p63 in the renewal of the adult prostate epithelium are likely to shed new light on the mechanisms involved in prostate carcinogenesis.     

survivin在非小细胞肺癌中的表达及其与bcl-2、p63表达的关系

目的：探讨survivin在非小细胞肺癌组织（non small cell lung cancer,NSCLC）中的表达,及其与bcl2、p63蛋白表达的相关性。方法：应用二步法免疫组织化法,检测survivin、bcl-2、p63蛋白在60例NSCLC组织和20例正常肺组织中的表达。结果：肺癌组织中的survivin蛋白阳性率（56．67％）明显高于正常肺组织15％）,有显著性差异;（p〈0．05）Ⅲ期surviving蛋白阳性表达率72．73％（16／22）明显高于Ⅰ＋Ⅲ期survivin47．37％（18／38）。有显著差异;（p〈0．05）survivin蛋白表达与患者年龄、病理类型、组织分化程度,淋巴结转移情况无关（P〉0．05）NSCLC组织bc 1-2蛋白表达阳性、阴性组中,survivin蛋白阳性表达率分别为66．67％（18／27）和48．48％（16／33）,两者比较,差异有显著性（P〈0．05）;p63蛋白表达阳性、阴性组中,survivin蛋白阳性表达率分别为53-33％（16／30）和60％（18／30）,两者比较,差异有显著性（P〈0．05）survivin,蛋白与bc1．2蛋白的表达呈正相关。survivin蛋白与p63蛋白的表达呈正相关。结论：survivin在NSCLC组织中表达上调,通过抑制细胞凋亡,在NSCLC的发生和发展中起到重要作用。survivin,bcl-2与p63它们分别在肺癌发生发展过程中不同途径上抑制肺癌细胞的凋亡,对肺癌早期诊断有一定的意义。对3种蛋白进行联合检测,更有利于肺癌的早期诊断和判断肺癌的分化程度、临床分期、淋巴结是否转移及病人的预后。survivin与bcl-2及survivin与p63可能起协同作用、并可能会成为NSCLC基因治疗的新靶点。     

A dominant negative form of p63 inhibits apoptosis in a p53-independent manner

Stem cells are a source of differentiated cells in multiple tissues. If genetic alterations occur in stem cells, the problem persists and malignant cancers may arise. DeltaNp63alpha-a homologue of the tumor suppressor p53-is exclusively expressed in proliferating undifferentiated epithelial cells and cancer cells of epidermal origin. Here, we show that DeltaNp63alpha antagonizes DNA damage-induced apoptosis in a p53-independent manner. We found that upon cellular injury, DeltaNp63alpha must be downregulated before apoptotic program can be activated. The 5637 cell line has abundant levels of DeltaNp63alpha and mutant p53, and it is resistant to DNA damage-induced apoptosis. The knockdown of DeltaNp63alpha by RNA interference sensitized these cells to apoptosis upon genotoxic insult. This suggests that DeltaNp63alpha plays an anti-apoptotic role regardless of the p53 status. Considering the frequent mutations of p53 in tumor cells, our results provide important implications for the treatment of cancers in which p63 is amplified.