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981.
Chi‐Tai Chiang Wing‐Keung Chu Shu‐Er Chow Jan‐Kan Chen 《Journal of cellular physiology》2009,219(1):117-122
p63 belongs to a member of the tumor suppressor protein p53 family. Due to alternative promoter usage, two types of p63 proteins are produced. The ΔNp63 isoform lacks the N‐terminal transactivation domain and is thought to antagonize TAp63 and p53 in target gene regulation. ΔNp63 has been found to be overexpressed in numerous human squamous cell carcinomas, including nasopharyngeal carcinoma (NPC). However, the role of ΔNp63 overexpression in NPC pathogenesis has not been clear. In this study, we use a ΔNp63 overexpressing human NPC cell line (NPC‐076) to explore the possible roles of ΔNp63 in cell proliferation and cell‐cycle regulation. We found that the proliferation of NPC‐076 cell is greatly suppressed when the overexpressed ΔNp63 is silenced by specific ΔNp63 siRNA. Further studies show that ΔNp63 silencing results in the upregulation of CKIs, including p27kip1 and p57kip2 in both mRNA and protein levels. Cell‐cycle analysis shows that ΔNp63 silencing also results in an increased G1 phase cell and apoptotic cell population. Our findings indicate that ΔNp63 plays important roles in the regulation of NPC‐076 cell‐cycle progression, and may play a role in the maintenance of NPC‐076 tumor cell phenotype. J. Cell. Physiol. 219: 117–122, 2009. © 2008 Wiley‐Liss, Inc. 相似文献
982.
983.
Bei-Bei Chu Liang Ge Chang Xie Yang Zhao Hong-Hua Miao Jing Wang Bo-Liang Li Bao-Liang Song 《The Journal of biological chemistry》2009,284(33):22481-22490
Niemann-Pick C1-like 1 (NPC1L1) plays a critical role in the enterohepatic absorption of free cholesterol. Cellular cholesterol depletion induces the transport of NPC1L1 from the endocytic recycling compartment to the plasma membrane (PM), and cholesterol replenishment causes the internalization of NPC1L1 together with cholesterol via clathrin-mediated endocytosis. Although NPC1L1 has been characterized, the other proteins involved in cholesterol absorption and the endocytic recycling of NPC1L1 are largely unknown. Most of the vesicular trafficking events are dependent on the cytoskeleton and motor proteins. Here, we investigated the roles of the microfilament and microfilament-associated triple complex composed of myosin Vb, Rab11a, and Rab11-FIP2 in the transport of NPC1L1 from the endocytic recycling compartment to the PM. Interfering with the dynamics of the microfilament by pharmacological treatment delayed the transport of NPC1L1 to the cell surface. Meanwhile, inactivation of any component of the myosin Vb·Rab11a·Rab11-FIP2 triple complex inhibited the export of NPC1L1. Expression of the dominant-negative mutants of myosin Vb, Rab11a, or Rab11-FIP2 decreased the cellular cholesterol uptake by blocking the transport of NPC1L1 to the PM. These results suggest that the efficient transport of NPC1L1 to the PM is dependent on the microfilament-associated myosin Vb·Rab11a·Rab11-FIP2 triple complex.Cholesterol homeostasis in human bodies is maintained through regulated cholesterol synthesis, absorption, and excretion. Intestinal cholesterol absorption is one of the major pathways to maintain cholesterol balance. NPC1L1 (Niemann-Pick C1-like protein 1), a polytopic transmembrane protein highly expressed in the intestine and liver, is required for dietary cholesterol uptake and biliary cholesterol reabsorption (1–4). Genetic or pharmaceutical inactivation of NPC1L1 significantly inhibits cholesterol absorption and confers the resistance to diet-induced hypercholesterolemia (1, 2, 4). Ezetimibe, an NPC1L1-specific inhibitor, is currently used to prevent and treat cardiovascular diseases (5).Human NPC1L1 contains 1,332 residues with 13 transmembrane domains (6). The third to seventh transmembrane helices constitute a conserved sterol-sensing domain (4, 7). NPC1L1 recycles between the endocytic recycling compartment (ERC)3 and the plasma membrane (PM) in response to the changes of cholesterol level (8). ERC is a part of early endosomes that is involved in the recycling of many transmembrane proteins. It is also reported that ERC is a pool for free cholesterol storage (9). When cellular cholesterol concentration is low, NPC1L1 moves from the ERC to the PM (8, 10). Under cholesterol-replenishing conditions, NPC1L1 and cholesterol are internalized together and transported to the ERC (8). Disruption of microfilament, depletion of the clathrin·AP2 complex, or ezetimibe treatment can impede the endocytosis of NPC1L1, thereby decreasing cholesterol internalization (8, 10, 11).The microfilament (MF) system, part of the cytoskeleton network, is required for multiple cellular functions such as cell shape maintenance, cell motility, mitosis, protein secretion, and endocytosis (12, 13). The major players in the microfilament system are actin fibers and motor proteins (14). Actin fibers form a network that serves as the tracks for vesicular transport (15, 16). Meanwhile, the dynamic assembly and disassembly of actin fibers and the motor proteins provides the driving force for a multitude of membrane dynamics including endocytosis, exocytosis, and vesicular trafficking between compartments (15, 16).Myosins are a large family of motor proteins that are responsible for actin-based mobility (14). Class V myosins (17, 18), comprising myosin Va, Vb, and Vc, are involved in a wide range of vesicular trafficking events in different mammalian tissues. Myosin Va is expressed mainly in neuronal tissues (19, 20), whereas myosins Vb and Vc are universally expressed with enrichment in epithelial cells (21, 22). Class V myosins are recruited to their targeting vesicles by small GTPase proteins (Rab) (23). Rab11a and Rab11 family-interacting protein 2 (Rab11-FIP2) facilitate the binding of myosin Vb to the cargo proteins of endocytic recycling vesicles (24–28).Myosin Vb binds Rab11a and Rab11-FIP2 through the C-terminal tail (CT) domain. The triple complex of myosin Vb, Rab11a, and Rab11-FIP2 is critical for endocytic vesicular transport and the recycling of many proteins including transferrin receptor (29), AMPA receptors (30), CFTR (28), GLUT4 (31, 32), aquaporin-2 (26), and β2-adrenergic receptors (33). The myosin Vb-CT domain (24) competes for binding to Rab11a and Rab11-FIP2 and functions as a dominant-negative form. Expression of the CT domain substantially impairs the transport of vesicles. Deficient endocytic trafficking is also observed in cells expressing the GDP-locked form of Rab11a (S25N) (34) or a truncated Rab11-FIP2, which competes for the rab11a binding (35).Here we investigated the roles of actin fibers and motor proteins in the cholesterol-regulated endocytic recycling of NPC1L1. Using pharmaceutical inactivation, dominant-negative forms, and an siRNA technique, we demonstrated that actin fibers and myosin Vb·Rab11a·Rab11-FIP2 triple complex are involved in the export of NPC1L1 to the PM and that this intact MF-associated triple complex is required for efficient cholesterol uptake. Characterization of the molecules involved in the recycling of NPC1L1 may shed new light upon the mechanism of cholesterol absorption. 相似文献
984.
Guo Li Xiao‐ai Zhang Hua Wang Xin Wang Chun‐ling Meng Chu‐yan Chan David Tai Wai Yew Kam Sze Tsang Karen Li Sau‐na Tsai Sai‐ming Ngai Zhong Chao Han Marie Chia‐mi Lin Ming‐liang He Hsiang‐fu Kung Professor 《Proteomics》2009,9(1):20-30
Umbilical cord (UC) and placenta (P) have been suggested as alternatives to bone marrow (BM) as sources of mesenchymal stem cells (MSC) for cell therapy, with both UC‐ and P‐MSC possess immunophenotypic and functional characteristics similar to BM‐MSC. However, their migration capacity, which is indispensable during tissue regeneration process, is unclear. Under defined conditions, the migration capacity of BM‐ and P‐MSC was found 5.9‐ and 3.2‐folds higher than that of UC‐MSC, respectively. By the use of 2‐DE and combined MS and MS/MS analysis, six differentially expressed proteins were identified among these MSC samples, with five of them known to be involved in cell migration as migration enhancing or inhibiting proteins. Consistent with their migration capacity, the levels of migration enhancing proteins including cathepsin B, cathepsin D and prohibitin,were significantly lower in UC‐MSC when compared with those in BM‐ and P‐MSC. For the migration inhibiting proteins such as plasminogen activator inhibitor‐1 (PAI‐1) and manganese superoxide dismutase, higher expression was found in the UC‐MSC. We also showed that the overexpression of the PAI‐1 impaired the migration capacity of BM‐ and P‐MSC while silencing of PAI‐1 enhanced the migration capacity of UC‐MSC. Our study indicates that PAI‐1 and other migration‐related proteins are pivotal in governing the migration capacity of MSC. 相似文献
985.
986.
987.
Tao Wang Kang Shao Qinying Chu Yanfei Ren Yiming Mu Lijia Qu Jie He Changwen Jin Bin Xia 《BMC bioinformatics》2009,10(1):83
Background
Spectral processing and post-experimental data analysis are the major tasks in NMR-based metabonomics studies. While there are commercial and free licensed software tools available to assist these tasks, researchers usually have to use multiple software packages for their studies because software packages generally focus on specific tasks. It would be beneficial to have a highly integrated platform, in which these tasks can be completed within one package. Moreover, with open source architecture, newly proposed algorithms or methods for spectral processing and data analysis can be implemented much more easily and accessed freely by the public. 相似文献988.
Background
Numerous proteins can be converted to amyloid-like fibrils to increase cytotoxicity and induce apoptosis, but the methods generally require a high concentration of protein, vigorous shaking, or fibril seed. As well, the detailed mechanism of the cytotoxic effects is not well characterized. In this study, we have developed a novel process to convert native proteins into the fibrillar form. We used globular bovine serum albumin (BSA) as a model protein to verify the properties of the fibrillar protein, investigated its cellular effects and studied the signaling cascade induced by the fibrillar protein. 相似文献989.
990.
Mitochondrial kinases in Parkinson’s disease: Converging insights from neurotoxin and genetic models
Alterations in mitochondrial biology have long been implicated in neurotoxin, and more recently, genetic models of parkinsonian neurodegeneration. In particular, kinase regulation of mitochondrial dynamics and turnover are emerging as central mechanisms at the convergence of neurotoxin, environmental and genetic approaches to studying Parkinson’s disease (PD). Kinases that localize to mitochondria during neuronal injury include mitogen activated protein kinases (MAPK) such as extracellular signal regulated protein kinases (ERK) and c-Jun N-terminal kinases (JNK), protein kinase B/Akt, and PTEN-induced kinase 1 (PINK1). Although site(s) of action within mitochondria and specific kinase targets are still unclear, these signaling pathways regulate mitochondrial respiration, transport, fission–fusion, calcium buffering, reactive oxygen species (ROS) production, mitochondrial autophagy and apoptotic cell death. In this review, we summarize accelerating experimental evidence gathered over the last decade that implicate a central role for kinase signaling at the mitochondrion in Parkinson’s and related neurodegenerative disorders. Interactions involving α-synuclein, leucine rich repeat kinase 2 (LRRK2), DJ-1 and Parkin are discussed. Converging mechanisms from different model systems support the concept of common pathways in parkinsonian neurodegeneration that may be amenable to future therapeutic interventions. 相似文献