p73:p53的类似物

p73是近来发现的与p5 3在结构与功能上非常相似的一个基因 ,位于 1p36。p73具有类似于p5 3的抑制细胞生长、促进凋亡的功能 ,还具有与p5 3不同的单基因表达方式 ,不与病毒癌蛋白相互作用。p73与肿瘤的关系密切 ,但到底是通过抑癌基因、癌基因 ,还是表基因机制在肿瘤的发生中起作用则尚未明确。     

p73-一个p53家族新基因

p73基因是一新发现的与经典抑癌基因p5 3具有相似结构、功能和活性的基因 ,并由于其在染色体上特殊的定位 ,被认为是一种新的候选抑癌基因。本文介绍了p73发现以来国外有关p73基因的研究进展 ,特别对p73基因的定位、p73与p5 3的关系、是否抑癌基因以及该基因在肿瘤发生发展中的作用和地位进行了综述。     

肺癌p73蛋白表达及其临床病理学意义

p73基因与p53基因同抑癌基因家族，p73蛋白在结构和功能上具有与p53蛋白高度相似性，都具有抑制肿瘤细胞生长、诱导细胞凋亡的功能。但两者双存在明显差异。文献报道，p73蛋白在一些癌细胞中呈高水平表达，与多种人类肿瘤的发生、发展密切相关。     

p73基因的研究进展

1997年 Kaghad等在 1p36区发现了 p73基因 ,其编码的 p73蛋白在结构与功能上与 p5 3蛋白均具有相似性 ,遂被认为是一候选的抑癌基因。但此后的一些研究资料对此又提出质疑。究竟 p73是 p5 3的“兄弟”还是“披着羊皮的狼”?其真正的作用还有待进一步研究     

p73基因与细胞凋亡

p73是经典抑癌基因p53的类似物。经研究证实，p73具有两面性。它可表达为两种相互独立却又密切相关的蛋白质即TApT3和DNp73。它们在细胞凋亡与肿瘤发生的过程中起着彼此对立以相互影响的作用。同时在细胞凋亡的过程中，p73的功能又受到E2F-1、C-Abl、C-Myc、P300、PKCδ等各种因素的影响。本文现就p73在细胞凋亡中的作用以及其影响因素作一综述。     

胰腺癌组织中p73和p63蛋白过表达的意义

研究表明，胰腺癌和人体其他部位的恶性肿瘤一样，其发生发展也是多基因异常改变的结果，虽然多数研究显示胰腺癌中抑癌基因p53的突变率较高（50％-80％），但p53蛋白的异常表达率与肿瘤的生物学行为和预后价值之间却未见明显的相关性。随着p53基因家族的两个新成员p73和p63基因（它们分别编码p73蛋白和p63蛋白）被相继发     

p73基因的研究进展

1997年Kaghad等在p73基因，其编码的p73蛋白在结构与功能上与p353蛋白均具有相似性，遂被认为是一候选的抑癌基因，但此后的一些研究资料对此又提出质疑。究竟p73是p53的“兄弟”还是“披着羊皮的狼”？其真正的作用还有等进一步研究。     

p73基因的研究进展

p73基因是p53家族的一个新成员 ,在结构和功能上与p53基因具有相似性。p73基因定位于1p3 6.3 3 ,具有四种转录剪切变异体 ,无肿瘤特异性的突变。p73基因过度表达时可激活特定的靶基因而抑制细胞生长和诱导凋亡。p73基因的转录激活作用受到许多因素影响。本文综述了p73基因功能与调控研究的最新进展。     

p53研究的新进展

肿瘤抑制基因p53是目前研究最为广泛和系统的抑癌基因之一。野生型p53(wt-p53)参与了DNA损伤修复、细胞周期调控、细胞凋亡及抑制血管生成等过程。p53基因的突变使上述功能丧失,从而导致肿瘤的形成。在大约50％人类肿瘤中可发现p53基因的突变,且几乎可见于各种类型的肿瘤细胞中。本文就目前p53研究及相关基冈治疗的进展作一综述。     

p73基因的分子生物学

从分子生物学水平对新发现的抑癌基因p73进行综述和报道。p73与p53在分子结构、基因功能和生物学活性等方面都具有同源性和相似性。p73的发现为癌症治疗提供了一条新途径。     

p73: structure and function

Alteration of the p53 tumor suppressor gene is a common, if not general, observation in human malignant tumors. p73 Is a novel member of the p53 family at chromosome 1p36.3, at which locus frequent defects are seen in many tumors including neuroblastoma. Besides structural similarities, the fact that p73 functions in the regulation of the cell cycle and apoptosis promotes the expansion of the research field concerning p53-associated tumor progression. In this paper, we review the structure and function of p73 as well as the mutational status in various human tumors. In addition, possibilities for new therapeutic applications with p73 for cancer cell control are discussed.     

Expression of p73 in normal skin and proliferative skin lesions

The p73 gene is a member of the p53 gene family and the structure and functions of p73 protein are similar to those of p53. However, these two proteins have different roles. In the present study, p73 protein was found immunohistochemically to be distributed in the basal cells of the epidermis, columnar basal cells in the hair follicle and peripheral cells without lipid droplets in the sebaceous and meibomian glands; it was expressed strongly in tumor cells in basal cell carcinomas and in the basal cell-like cells in seborrheic keratosis, and weakly or negatively in the squamous cell-like cells in seborrheic keratosis and in the tumor cells in squamous cell carcinomas. No relationship was detected between p73 and p53 protein distribution and between p73 protein expression and the proliferative potential, as shown by the Ki-67 immunopositive cell ratio. The present study shows that p73 protein is likely to play important roles in skin differentiation rather than proliferation or carcinogenesis of the skin.     

A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73

Protein degradation is an essential and highly regulated process. The proteasomal degradation of the tumor suppressors p53 and p73 is regulated by both polyubiquitination and by an ubiquitin-independent process. Here, we show that this ubiquitin-independent process is mediated by the 20S proteasomes and is regulated by NQO1. NQO1 physically interacts with p53 and p73 in an NADH-dependent manner and protects them from 20S proteasomal degradation. Remarkably, the vast majority of NQO1 in cells is found in physical association with the 20S proteasomes, suggesting that NQO1 functions as a gatekeeper of the 20S proteasomes. We further show that this pathway plays a role in p53 accumulation in response to ionizing radiation. Our findings provide the first evidence for in vivo degradation of p53 and p73 by the 20S proteasomes and its regulation by NQO1 and NADH level.     

Serous papillary carcinoma of the endometrium arising from endometrial polyps: a clinical, histological, and immunohistochemical study of 13 cases

Serous papillary carcinoma is an aggressive tumor. Point mutations in the p53 suppressor gene might explain in part the rapid growth of this malignant tumor and its unfavorable outcome. The aims of this study were to evaluate the behavior of serous papillary carcinoma developing in endometrial polyps and to assess the p53 protein overexpression. Patients included in this study were treated in our institution between 1982 and 2003. All clinical and pathological materials were examined. A p53 protein immunohistochemical analysis was performed on paraffin-embedded tissues. Thirteen serous papillary carcinomas arising from benign polyps of the endometrium were identified. The patients' age averaged 73 years. All patients were treated surgically. After an average follow-up of 22 months, 54% of the patients were dead or alive with disease. Of 10 serous papillary carcinomas, 8 (80%) for which paraffin blocks were available overexpressed the p53 protein. A serous papillary carcinoma arising from benign polyps of the endometrium remains a malignant neoplasia with an unfavorable outcome even if the primary tumor is limited to the polyp. The high rate of protein p53 overexpression suggests that a p53 gene mutation occurs early in the disease and might explain the rapid growth of the tumor.     

Expression profiles and functional implications of p53-like transcription factors in thymic epithelial cell subtypes

In this study, we investigated the localization and functional significance of p53 tumor suppressor-like molecules, p63 and p73, in human thymic epithelial cells (TECs). Immunohistochemical studies showed particular distribution profiles of p63 and p73 in thymic epithelium, in which cortical TECs preferentially expressed p63 in their nuclei whereas subcapsular and medullary TECs expressed both p63 and p73 in their nuclei. The wide distribution of p63 in TECs was further suggested by studies using TECs of primary culture. In vitro studies using two human TEC lines demonstrated that p63 was capable of up-regulating intercellular adhesion molecule-1 (ICAM-1) and enhancing the production of IL-6 and IL-8. Moreover, in vitro studies also indicated that p73, but not p63, had the capacity to induce granulocyte macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) in the TEC lines. These findings suggest that p63 would regulate the cell adhesive property through ICAM-1/LFA-1 interaction and the production of IL-6 and IL-8, probably in all TEC subtypes. p73 in subcapslar and medullary TECs was suggested to play a role in the regulation of the production of GM-CSF and G-CSF, which might stimulate other stromal cells such as dendritic cells, macrophages and endothelial cells around these regions.     

Validation of MdmX as a therapeutic target for reactivating p53 in tumors

MdmX, also known as Mdm4, is a critical negative regulator of p53, and its overexpression serves to block p53 tumor suppressor function in many cancers. Consequently, inhibiting MdmX has emerged as an attractive approach to restoring p53 function in those cancers that retain functional p53. However, the consequences of acute systemic MdmX inhibition in normal adult tissues remain unknown. To determine directly the effects of systemic MdmX inhibition in normal tissues and in tumors, we crossed mdmX(-/-) mice into the p53ER(TAM) knockin background. In place of wild-type p53, p53ER(TAM) knockin mice express a variant of p53, p53ER(TAM), that is completely dependent on 4-hydroxy-tamoxifen for its activity. MdmX inhibition was then modeled by restoring p53 function in these MdmX-deficient mice. We show that MdmX is continuously required to buffer p53 activity in adult normal tissues and their stem cells. Importantly, the effects of transient p53 restoration in the absence of MdmX are nonlethal and reversible, unlike transient p53 restoration in the absence of Mdm2, which is ineluctably lethal. We also show that the therapeutic impact of restoring p53 in a tumor model is enhanced in the absence of MdmX, affording a significant extension of life span over p53 restoration in the presence of MdmX. Hence, systemic inhibition of MdmX is both a feasible therapeutic strategy for restoring p53 function in tumors that retain wild-type p53 and likely to be significantly safer than inhibition of Mdm2.     

Altered senescence, apoptosis, and DNA damage response in a mutant p53 model of accelerated aging

The tumor suppressors p16^INK4a and p53 have been implicated as contributors to age-associated stem cell decline. Key functions of p53 are the induction of cell cycle arrest, senescence, or apoptosis in response to DNA damage. Here, we examine senescence, apoptosis, and DNA damage responses in a mouse accelerated aging model that exhibits increased p53 activity, the p53^+/m mouse. Aged tissues of p53^+/m mice display higher percentages of senescent cells (as determined by senescence-associated β-galactosidase staining and p16^INK4a and p21 accumulation) compared to aged tissues from p53^+/+ mice. Surprisingly, despite having enhanced p53 activity, p53^+/m lymphoid tissues exhibit reduced apoptotic activity in response to ionizing radiation compared to p53^+/+ tissues. Ionizing radiation treatment of p53^+/m tissues also induces higher and prolonged levels of senescence markers p16^INK4a and p21, suggesting that in p53^+/m tissues the p53 stress response is enhanced and is shifted away from apoptosis toward senescence. One potential mechanism for accelerated aging in the p53^+/m mouse is a failure to remove damaged or dysfunctional cells (including stem and progenitor cells) through apoptosis. The increased accumulation of dysfunctional and senescent cells may contribute to reduced tissue regeneration, tissue atrophy, and some of the accelerated aging phenotypes in p53^+/m mice.     

p73：人类非小细胞肺癌细胞株中的肿瘤抑制基因(英文)

目的：p73基因是与p53相类似的基因,在人类神经母细胞瘤中被假定作为肿瘤抑制基因。为了证实p73在非小细胞肺癌中是否也是肿瘤抑制基因，我们应用StyⅠ内切酶多态分析法研究了6株非小细胞肺癌细胞的等位基因表达模式。方法：利用RT-PCR检测p73基因在这6株肺癌细胞中转录水平的表达，同时用免疫组织化学方法检测5株非小细胞肺癌细胞所诱发的裸鼠种植瘤中P73蛋白的表达。结果：p73基因在这6株非小细胞肺癌中均为纯合性等位基因表达，而GC/GC基因型为主要类型。p73基因在转录水平和蛋白水平完全丧失表达。结论：根据实验结果可推测，p73在这6株非小细胞肺癌细胞中仍扮演了肿瘤抑制基因的角色。