分化抑制因子与肿瘤相关性研究进展

分化抑制因子(inhibitor of differentiationl Id)是广泛表达的螺旋-环-螺旋(helix-loop-helix,HLH)家族成员中参与负性调节的转录因子,在真核生物中,Id蛋白在发育、调控细胞增殖和分化、肿瘤血管形成、侵袭性以及转移等方面有着重要的作用.最近的研究表明,Id表达不仅和肿瘤形成、进展以及预后相关,而且有望成为肿瘤治疗的新靶点.综述了Id在肿瘤发生发展过程中可能的机制、作用以及在肿瘤靶向治疗中的前景.     

Twist1在肿瘤发生中的作用

Twist1作为bHLH转录因子起初被发现在胚胎发育中起关键作用. 最近10年研究证明,它在多种癌的发生、发展中发挥重要作用. 本文结合多种信号通路（如MAPK、STAT、NF κB）以及与其基因表达调控相关的转录因子、翻译后修饰、microRNA等综述Twist1表达调节. 同时,根据其参与癌的发展及作用方式,结合细胞间联系、肿瘤微环境、侵袭和迁移、化疗抗性、上皮 间质转化（EMT）、细胞衰老与程序性死亡、肿瘤干细胞等,概括Twist1在肿瘤发生中的作用.     

卵泡抑素相关蛋白的病理生理功能

卵泡抑素相关蛋白(follistatin related protein,FRP)是一种细胞外基质糖蛋白,该蛋白参与细胞增殖、迁移、组织重塑、胚胎发育、细胞间相互作用及多种病理生理过程.近年研究显示,该蛋白同时具有抑制细胞凋亡和抑制细胞增殖的双重功能:在心肌缺血的动物模型中,FRP被证实有保护心肌细胞、抗凋亡、促进内皮细胞增殖等功能;FRP也可由血管平滑肌细胞合成分泌,并具有反馈调节平滑肌细胞功能的作用,该蛋白还可抑制多种肿瘤细胞增殖.     

c-myb转录因子在细胞中作用机制研究进展

转录因子c-myb最初发现与造血器官调控密切相关,且对于多种肿瘤发生发展必不可少,如在乳腺癌、大肠癌等肿瘤中调节细胞增殖、分化。因此,转录因子c-myb被认为是肿瘤治疗潜在靶标。本文综合介绍了c-myb转录因子结构、功能及其在相关肿瘤发生发展中作用以及探索如何进行c-myb靶向治疗。     

JunD的结构功能特征及其在肿瘤发展中的作用

JunD是一种属于多功能激活剂蛋白-1（activating protein-1,AP-1) 家族的转录因子,可以激活或抑制多种靶基因的表达.在生长发育过程中,在各种细胞类型中都呈现出组成性表达.近20年的临床数据及分子生物学研究表明,JunD蛋白的功能受多个复杂过程调控,包括转录控制、转录后调节、蛋白质翻译后修饰及蛋白-蛋白相互作用等.JunD基因表达的精细调控及JunD蛋白与其它蛋白之间的相互作用可调节细胞增殖、分化和凋亡等过程.JunD蛋白活性异常会导致肿瘤、代谢及病毒类疾病的发生.JunD蛋白的转录激活及抑制受1个复杂调控网络调控,在这个网络调节下,JunD蛋白在细胞的生长调控过程中发挥重要作用.本文就JunD基因表达的调控机制及其与肿瘤之间关系的最新研究进展做一综述.     

JMJ在胚胎发育中的作用

胚胎发育是一个连续、复杂的过程,涉及到多种基因的参与。JMJ是广泛存在的转录抑制因子,包括核定位信号区、转录抑制区、DNA结合区,是富含A/T相互作用因子家族中的一员。它通过与一些转录调控蛋白的相互作用调节细胞生长和基因转录,在胚胎器官形态形成中发挥重要的作用。     

转录因子叉头框K1在肿瘤中的作用

叉头框K(forkhead box class K,FOXK)蛋白家族是一类进化保守的转录因子,近年来被认为是多种癌症的关键转录调控因子.FOXK家族成员参与介导了广泛的生物学过程,包括细胞增殖、分化、凋亡、自噬、细胞周期、DNA损伤和肿瘤发生.FOXK1基因作为转录因子参与了多种肿瘤发生、发展等过程的调控,其基因结构...     

抗酶抑制因子结构、功能与代谢的研究进展

抗酶抑制因子是一种热不稳定蛋白,与鸟氨酸脱羧酶同源,但不具有鸟氨酸脱羧酶活性,经泛素依赖途径被降解.抗酶抑制因子与抗酶高度亲和,抑制抗酶功能,恢复鸟氨酸脱羧酶活性.研究发现,抗酶抑制因子还能够调节多胺转运,抑制细胞周期蛋白D1的降解,以及加速中心粒复制,从而促进细胞增殖及肿瘤发生.     

叉头框(Fox)转录因子家族的结构与功能

叉头框(forkheadbox,Fox)蛋白家族是一类DNA结合区具有翼状螺旋结构的转录因子,目前已有17个亚族。Fox蛋白不仅能作为典型的转录因子通过招募共激活因子等调节基因转录,有些还能直接同凝聚染色质结合参与其重构,协同其他转录因子参与转录调节。PI3K-Akt/PKB、TGFβ-Smad和MAPKinase等多条信号通路都可以影响Fox蛋白的磷酸化水平,从而调节其活性。Fox蛋白在胚胎发育、细胞周期调控、糖类和脂类代谢、生物老化和免疫调节等多种生物学过程中发挥作用。     

Ski在细胞增殖、转化、胶原分泌和炎性反应中的调节作用

ski是病毒癌基因v-ski的细胞内同源物,其蛋白产物Ski参与了造血细胞增殖、肌肉再生、骨和神经系统发育和突触投射以及组织创伤愈合、纤维化、肿瘤发生及增殖等多种生理病理过程。Ski作为一个多功能的转录调节因子,参与了多种分子信号的调节。该文将对Ski在细胞增殖、转化、胶原分泌和炎性反应中的调节作用及机制进行综述。     

Geminin Coordinates Cell Cycle and Developmental Control

Growth and differentiation are two major themes in embryonic development. Numerous cell divisions have to be regulated on the path from a unicellular embryo, the zygote, to the multicellular structures of a mature being. Numerous functions, specializations and cellular identities have to be generated, in order to form a complex and mature animal. Numerous mechanisms have to control the correct assignment and acquisition of cellular fates, as well as the right timing and allocation of cells. Therefore, a strict coordination has to occur between embryonic patterning and the cell cycle. From this point of view, dual roles or mutual interactions of typical proliferation and developmental control genes are likely. Recently, new light was shed on these issues by identifying the nuclear protein Geminin as a molecular coordinator between the cell cycle and axial patterning. We summarize the role of Geminin in cell cycle, in the embryonic patterning controlled by Hox genes, providing insights into cell cycle regulators in embryonic development, and, conversely, typical developmental control genes in cell cycle regulation.     

Increased expression of geminin stimulates the growth of mammary epithelial cells and is a frequent event in human tumors

Geminin is a potent inhibitor of origin assembly and re-replication in multicellular eukaryotes and is a negative regulator of DNA replication during the cell cycle. Thus, it was proposed as an inhibitor of cell proliferation and as a potential tumor suppressor gene. However, the protein was found specifically expressed in proliferating lymphocytes and epithelial cells and up-regulated in several malignancies. Therefore, geminin is now regarded as an oncogene but its role in tumor development remains unknown. In this study, we evaluated by Western blot analysis the expression of geminin in a series of human cancer cell lines of various histogenetic origin and in a series of human primary colon, rectal, and breast cancers. Expression of geminin was variable in different cell lines and not related to the expression level of the corresponding mRNA. Moreover, geminin was expressed at higher level in 56% and 58% of colon and rectal cancers, respectively, compared with the corresponding adjacent normal mucosa. A high expression of geminin was also detected by immunohistochemistry in 60% of human primary breast cancers. We also transfected a full-length geminin cDNA in a human non-tumorigenic and a cancer breast cell lines and obtained derivatives expressing high levels of the protein. Geminin overexpression stimulated cell cycle progression and proliferation in both normal and cancer cells and increased the anchorage--independent growth of breast cancer cells. These results demonstrate that expression of geminin is frequently deregulated in tumor cells and might play an important role in the regulation of cell growth in both normal and malignant cells.     

A benzoxazine derivative specifically inhibits cell cycle progression in p53-wild type pulmonary adenocarcinoma cells

A fundamental aspect of cancer development is cancer cell proliferation. Seeking for chemical agents that can interfere with cancer cell growth has been of great interest over the years. In our study, we found that a benzoxazine derivative, (6-tert-butyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) methanol (TBM), could inhibit cell growth and caused significant cell cycle arrest in pulmonary adenocarcinoma A549 and H460 cells with wild-type p53, while not affecting the cell cycle distribution in p53-deleted H1299 lung adenocarcinoma cells. Since P53 plays an important role in regulating cell cycle progression, we analyzed the protein level of p53 by Western blot, and detected a significant elevation of p53 level after TBM treatment in A549 and H460 cells. The data suggested that TBM might specifically inhibit the proliferation of p53 wild-type lung adenocarcinoma cells through a p53-dependent cell cycle control pathway. More interestingly, results indicated that TBM might serve as a useful tool for studying the molecular mechanisms of lung cancer cell growth and cell cycle control, especially for the biologic process regulated by P53.     

Cell cycle regulator geminin is dispensable for the proliferation of vascular smooth muscle cells

The proliferation of vascular smooth muscle cells (VSMCs) plays a major role in the pathogenesis of many cardiovascular diseases. Geminin regulates DNA replication and cell cycle progression and plays a key role in the proliferation of cancer cells. We therefore hypothesized that geminin regulates the proliferation of VSMCs. The present study demonstrates that the level of geminin expression was low in quiescent VSMCs (approximately 90% and 10% of cells in the G1 and in S/G2/M phases of the cell cycle, respectively), increased as more cells entered in S/G2/M, and then decreased as cells exited S/G2/M. Further, angiotensin II and norepinephrine stimulated expression of geminin in VSMCs. However, the DNA content, nuclear morphology, percentage of cells at different stages of the cell cycle, and rate of proliferation of VSMCs from which geminin was either depleted or overexpressed were all similar. These findings indicate geminin functions differently in VSMCs than it does in cancer cell lines and that it may provide a target for treating cancers without affecting normal cells.     

Kinases as targets in the treatment of solid tumors

The protein kinase family, one of the largest gene families in eukaryotes, plays an important role in regulating various cellular processes such as cell proliferation, cell death, cell cycle progression, differentiation and cell survival. Therefore, it is not surprising that the deregulation of many kinases is usually directly linked to cancer development. In all solid tumors, changes in protein kinase expression levels and activities, as well as alterations in the degree of posttranslational modifications can contribute to cancer development. Consequently, the identification of molecular targets and signaling pathways specific to cancer cells is becoming more and more important for cancer drug development and cancer therapies. Inhibition of various protein kinases has already been investigated in many pre-clinical and clinical trials targeting all stages of signal transduction, demonstrating promising results in cancer therapy. Conventional chemotherapeutics are often ineffective as well as harmful; hence a combination of both chemotherapeutics and protein kinase inhibitors may result in new and more successful therapeutic approaches. In this review we focus on protein kinases involved in different signaling pathways and their alterations in solid tumors.