p57KIP2

p57kip2
  • 文章类型: Journal Article
    为了在体外产生足够数量的可移植造血干细胞(HSC),详细了解这个过程是如何在体内发生的是至关重要的。内皮到造血系统的转变(EHT),最终产生了第一批HSC,是一个非常复杂的过程,在这个过程中,关键调节器在精确的时刻打开和关闭,并嵌入到来自周围细胞和组织的无数微环境信号中。我们以前已经证明了交感神经系统和主动脉下间质内GATA3的HSC支持功能,但在这里表明它在EHT期间也起着细胞内在的作用。它在血源性内皮细胞和早期HSC前体中表达,其中它的表达与更静止的状态相关。重要的是,Gata3的内皮特异性缺失表明,这些细胞在功能上需要成熟为HSC,将GATA3置于EHT监管网络的核心。
    To generate sufficient numbers of transplantable hematopoietic stem cells (HSCs) in vitro, a detailed understanding of how this process takes place in vivo is essential. The endothelial-to-hematopoietic transition (EHT), which culminates in the production of the first HSCs, is a highly complex process during which key regulators are switched on and off at precise moments, and that is embedded into a myriad of microenvironmental signals from surrounding cells and tissues. We have previously demonstrated an HSC-supportive function for GATA3 within the sympathetic nervous system and the sub-aortic mesenchyme, but show here that it also plays a cell-intrinsic role during the EHT. It is expressed in hemogenic endothelial cells and early HSC precursors, where its expression correlates with a more quiescent state. Importantly, endothelial-specific deletion of Gata3 shows that it is functionally required for these cells to mature into HSCs, placing GATA3 at the core of the EHT regulatory network.
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  • 文章类型: Journal Article
    Androgenetic complete hydatidiform moles (CHMs) are associated with an increased risk of gestational trophoblastic neoplasia. P57KIP2 expression in hydatidiform moles is thought to be a powerful marker for differentiating CHMs from partial hydatidiform moles (PHMs). However, since there are so few such families clinically, very few studies have addressed the importance of p57KIP2-positive in the diagnosis and prognosis of CHM. This study aimed to emphasize the significance of the accurate diagnosis of rare CHM and careful follow-up. The classification of the hydatidiform mole was based on morphologic examination and p57KIP2 expression was determined by p57KIP2 immunohistochemical staining. Copy number variation sequencing was used to determine the genetic make-up of the mole tissues. In addition, the short tandem repeat polymorphism analysis was used to establish the parental origin of the moles. Finally, whole-exome sequencing was performed to identify the causal genetic variants associated with this case. In one Chinese family, the proband had numerous miscarriages throughout her two marriages. Morphologic evaluation and molecular genotyping accurately sub-classified two molar specimens as uniparental disomy CHM of androgenetic origin. Furthermore, p57KIP2 expression was found in cytotrophoblasts and villous stromal cells. In the tissue, there were hyperplasia trophoblastic cells and heteromorphic nuclei. In this family, no deleterious variant genes associated with recurrent CHM were detected. It is important to evaluate the prognostic value of p57KIP2 expression in androgenetic recurrent CHM. This knowledge may help to minimize erroneous diagnosis of CHMs as PHMs, as well as making us aware of the need to manage potential gestational trophoblastic neoplasia.
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  • 文章类型: Journal Article
    目的:研究kobusone降低高糖水平和促进β细胞增殖的能力。
    方法:将四周大的雌性db/db小鼠分配给kobusone(25mg/kg体重,每天两次腹膜内)或对照组(相同体积的PBS)。每周两次测量葡萄糖水平和体重。6周后,进行了腹膜内葡萄糖耐量试验和免疫组织化学研究,并测定胰岛素水平。参与细胞增殖的mRNA的表达,例如PI3K,Akt,通过定量逆转录聚合酶链反应(RT-qPCR)测量细胞周期蛋白D3和p57Kip2。
    结果:与溶媒相比,Kobusone降低了3周后的血糖水平,并更强烈地增加了血清胰岛素水平。免疫组织化学显示,kobusone增加5-溴-2'-脱氧尿苷掺入胰岛β细胞,表明它可以在体内刺激胰岛β细胞复制。RT-qPCR表明,kobusone上调PI3K的mRNA表达,Akt,和细胞周期蛋白D3,并下调p57Kip2的表达。
    结论:我们的研究结果表明,kobusone是一种有效的胰岛β细胞诱导剂,具有开发作为抗糖尿病药物的潜力。
    OBJECTIVE: To investigate the ability of kobusone to reduce high glucose levels and promote β-cell proliferation.
    METHODS: Four-week-old female db/db mice were assigned to the kobusone (25 mg/kg body weight, intraperitoneally twice a day) or control group (same volume of PBS). Glucose levels and body weight were measured twice a week. After 6 weeks, intraperitoneal glucose tolerance tests and immunohistochemical studies were performed, and insulin levels were determined. The expression of mRNAs involved in cell proliferation, such as PI3K, Akt, cyclin D3 and p57Kip2, was measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR).
    RESULTS: Kobusone reduced blood glucose levels after 3 weeks and more strongly increased serum insulin levels than the vehicle. Immunohistochemistry illustrated that kobusone increased 5-bromo-2\'-deoxyuridine incorporation into islet β-cells, suggesting that it can stimulate islet β-cell replication in vivo. RT-qPCR indicated that kobusone upregulated the mRNA expression of PI3K, Akt, and cyclin D3 and downregulated that of p57Kip2.
    CONCLUSIONS: Our findings suggest that kobusone is a potent pancreatic islet β-cell inducer that has the potential to be developed as an anti-diabetic agent.
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  • 文章类型: Journal Article
    p57Kip2蛋白是CIP/Kip家族的成员,主要位于细胞核中,发挥其Cyclin/CDKs抑制功能。此外,蛋白质在胚胎发育中起关键作用,分化,和致癌作用取决于其细胞定位和相互作用。CDKN1C突变,编码人类p57Kip2的基因,导致不同遗传疾病的发展,包括Beckwith-Wiedemann,图像和银罗素综合征。我们研究了特定的Beckwith-Wiedemann相关的CDKN1C变化(c.946C>T),该变化导致C端氨基酸(精氨酸316)被色氨酸(R316W-p57Kip2)取代。我们发现R316W-p57Kip2有明显的再分布,而野生型p57Kip2主要发生在细胞核中,突变形式也分布在细胞质中。转染编码p57Kip2N-和C-末端结构域的两个表达构建体,分别,允许在残基220-316之间映射核定位信号(NLS)。此外,通过去除蛋白质C末端的基本RKRLR序列(从312到316个残基),p57Kip2被限制在细胞质中,暗示这个序列是核进入绝对必需的。总之,我们发现了一个未报告的p57Kip2NLS,并提示其缺失或突变可能与CDKN1C相关人类疾病相关,决定了p57Kip2定位/调控作用的显著变化.
    p57Kip2 protein is a member of the CIP/Kip family, mainly localized in the nucleus where it exerts its Cyclin/CDKs inhibitory function. In addition, the protein plays key roles in embryogenesis, differentiation, and carcinogenesis depending on its cellular localization and interactors. Mutations of CDKN1C, the gene encoding human p57Kip2, result in the development of different genetic diseases, including Beckwith-Wiedemann, IMAGe and Silver-Russell syndromes. We investigated a specific Beckwith-Wiedemann associated CDKN1C change (c.946 C>T) that results in the substitution of the C-terminal amino acid (arginine 316) with a tryptophan (R316W-p57Kip2). We found a clear redistribution of R316W-p57Kip2, in that while the wild-type p57Kip2 mostly occurs in the nucleus, the mutant form is also distributed in the cytoplasm. Transfection of two expression constructs encoding the p57Kip2 N- and C-terminal domain, respectively, allows the mapping of the nuclear localization signal(s) (NLSs) between residues 220-316. Moreover, by removing the basic RKRLR sequence at the protein C-terminus (from 312 to 316 residue), p57Kip2 was confined in the cytosol, implying that this sequence is absolutely required for nuclear entry. In conclusion, we identified an unreported p57Kip2 NLS and suggest that its absence or mutation might be of relevance in CDKN1C-associated human diseases determining significant changes of p57Kip2 localization/regulatory roles.
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  • 文章类型: Journal Article
    Postnatal growth restriction (PGR) increases the risk for cardiovascular disease (CVD) in adulthood, yet there is minimal mechanistic rationale for the observed pathology. The purpose of this study was to identify proteomic differences in hearts of growth-restricted and unrestricted mice, and propose mechanisms related to impairment in adulthood. Friend leukemia virus B (FVB) mouse dams were fed a control (CON: 20% protein), or low-protein (LP: 8% protein) isocaloric diet 2 weeks before mating. LP dams produce 20% less milk, inducing growth restriction. At birth (postnatal; PN1), pups born to dams fed the CON diet were switched to LP dams (PGR group) or a different CON dam. At PN21, a sub-cohort of CON (n = 3 males; n = 3 females) and PGR (n = 3 males; n = 3 females) were euthanized and their proteome analyzed by two-dimensional differential in-gel electrophoresis (2D DIGE) and mass spectroscopy. Western blotting and silver nitrate staining confirmed 2D DIGE results. Littermates (CON: n = 4 males and n = 4 females; PGR: n = 4 males and n = 4 females) were weaned to the CON diet. At PN77, echocardiography measured cardiac function. At PN80, hearts were removed for western blotting to determine if differences persisted into adulthood. 2D DIGE and western blot confirmation indicated PGR had reductions in p57kip2, Titin (Ttn), and Collagen (Col). At PN77, PGR had impaired cardiac function as measured by echocardiography. At PN80, western blots of p57kip2 showed protein abundance recovered from PN21. PN80 silver staining of large molecular weight proteins (Ttn and Col) was reduced in PGR. PGR reduces cell cycle activity at PN21, which is recovered in adulthood. However, collagen fiber networks are altered into adulthood.
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  • 文章类型: Journal Article
    The cyclin/CDK inhibitor p57Kip2 belongs to the Cip/Kip family, with p21Cip1 and p27Kip1, and is the least studied member of the family. Unlike the other family members, p57Kip2 has a unique role during embryogenesis and is the only CDK inhibitor required for embryonic development. p57Kip2 is encoded by the imprinted gene CDKN1C, which is the gene most frequently silenced or mutated in the genetic disorder Beckwith-Wiedemann syndrome (BWS), characterized by multiple developmental anomalies. Although initially identified as a cell cycle inhibitor based on its homology to other Cip/Kip family proteins, multiple novel functions have been ascribed to p57Kip2 in recent years that participate in the control of various cellular processes, including apoptosis, migration and transcription. Here, we will review our current knowledge on p57Kip2 structure, regulation, and its diverse functions during development and homeostasis, as well as its potential implication in the development of various pathologies, including cancer.
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  • 文章类型: Journal Article
    In numerous instances, the fate of a single cell not only represents its peculiar outcome but also contributes to the overall status of an organism. In turn, the cell division cycle and its control strongly influence cell destiny, playing a critical role in targeting it towards a specific phenotype. Several factors participate in the control of growth, and among them, p27Kip1 and p57Kip2, two proteins modulating various transitions of the cell cycle, appear to play key functions. In this review, the major features of p27 and p57 will be described, focusing, in particular, on their recently identified roles not directly correlated with cell cycle modulation. Then, their possible roles as molecular effectors of polyphenols\' activities will be discussed. Polyphenols represent a large family of natural bioactive molecules that have been demonstrated to exhibit promising protective activities against several human diseases. Their use has also been proposed in association with classical therapies for improving their clinical effects and for diminishing their negative side activities. The importance of p27Kip1 and p57Kip2 in polyphenols\' cellular effects will be discussed with the aim of identifying novel therapeutic strategies for the treatment of important human diseases, such as cancers, characterized by an altered control of growth.
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  • 文章类型: Journal Article
    Lithium salt is the first-line therapeutic option for bipolar disorder and has been proposed as a potential antitumoral drug. The effects of LiCl treatment were investigated in SH-SY5Y, a human neuroblastoma cell line and an in vitro model of dopaminergic neuronal differentiation. LiCl, at the dosage used in psychiatric treatment, does not affect cell proliferation, while at higher doses it delays the SH-SY5Y cell division cycle and for prolonged usage reduces cell viability. Moreover, the ion treatment affects DNA integrity as demonstrated by accumulation of p53 and γH2AX (the phosphorylated form of H2AX histone), two important markers of genome damage. p57Kip2, a CIP/Kip protein, is required for proper neuronal maturation and represents a main factor of response to stress including genotoxicity. We evaluated the effect of lithium on p57Kip2 levels. Unexpectedly, we found that lithium downregulates the level of p57Kip2 in a dose-dependent manner, mainly acting at the transcriptional level. A number of different approaches, mostly based on p57Kip2 content handling, confirmed that the CKI/Kip reduction plays a key role in the DNA damage activated by lithium and suggests the unanticipated view that p57Kip2 might be involved in DNA double-strand break responses. In conclusion, our study identified novel roles for p57Kip2 in the molecular mechanism of lithium at high concentration and, more in general, in the process of DNA repair.
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    文章类型: Journal Article
    BACKGROUND: Colorectal cancer is still one of the main causes of cancer death in the world. There is a continous need for novel biomarkers for diagnose, treatment modalities and follow-up. Cyclin E and p57KIP2 as the positive and negative regulators of cell cycle seem to be an important target for investigations.
    METHODS: In a retrospective setting, primary colorectal adenocarcinoma cases examined in Mustafa Kemal University, School of Medicine, Pathology Department between 2008-2015 were reviewed. Immunohistochemical expressions of cyclin E and p57KIP2 in 80 pairs of colorectal carcinoma and adjacent normal mucosal tissues were evaluated and the findings were compared with clinicopathological parameters and survival time.
    RESULTS: There were no statistically significant difference between two groups both in cyclin E and p57KIP2 stained tissues (P>0.05). There were 40 (50%) patients in high-expression group and 40 (50%) patients in low-expression group for cyclin E. p57KIP2 was negative in 55 (68.75%) patients and positive in 25 (31.75%) patients. There were no statistically significant relation between p57KIP2 and cyclin E expressions with clinicopathologic parameters defined as age, gender, lymphovascular invasion, perineural invasion, depth of invasion, nodal involvement, emergency in operation, perforation before operation and overall survival except that there was significant relation between p57KIP2 expression and histological grade (P=0.012).
    CONCLUSIONS: Immunohistochemical studies of cyclin E and p57KIP2 should be performed with larger series of patients supported by more detailed technical research methods to be candidates as predictive markers for treatment modalities and prognostic factors.
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  • 文章类型: Journal Article
    OBJECTIVE: The aim of this study was to identify a co-existing hydatidiform mole (HM) in twin pregnancy from the abnormal mixed-genomic products of conception (POC) after assisted reproduction by histopathological review, evaluation of p57kip2 immunostaining and short tandem repeat genotyping.
    METHODS: Thirty-seven patients were collected with suspicion for HM by pathological morphology. They had two embryos individually transferred to their uterus after in vitro fertilization and presented two gestational sacs with undeveloped embryos or one sac with an abnormal area by ultrasonography.
    RESULTS: Thirty patients were diagnosed as singleton pregnancy, including twenty-two non-molar gestations, six trisomy gestations, one homozygous complete mole and one heterozygous partial mole. Although six patients had ultrasonic imaging of two gestational sacs, the embryonic components in the vacant sac might fade away after transferring. Other seven patients were considered as twin pregnancy by the allelic genotype from two individual conceptions. For the patients with uniform p57kip2 positivity, excessive paternal alleles indicated the potential partial HM in the twin pregnancy. For the patients demonstrated divergent and/or discordant p57kip2 immunostaining, twin pregnancy with co-existing complete HM or mosaic conception were confirmed by genotyping of different villi population respectively. These patients were monitored by serum β-HCG, while one twin pregnancy with complete mole suffered invasive mole and received chemotherapy.
    CONCLUSIONS: A strategy composed of selective clinicopathological screening, immunohistochemical interpretation and accurate genotyping is recommended for diagnostically challenging mixed-genomic POC of potential twin pregnancy with HM, especially to differentiate a non-molar mosaic conception from a partial mole.
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