全文获取类型
收费全文 | 2285篇 |
免费 | 17篇 |
国内免费 | 11篇 |
出版年
2023年 | 4篇 |
2022年 | 7篇 |
2021年 | 19篇 |
2020年 | 26篇 |
2019年 | 28篇 |
2018年 | 42篇 |
2017年 | 30篇 |
2016年 | 18篇 |
2015年 | 111篇 |
2014年 | 316篇 |
2013年 | 277篇 |
2012年 | 312篇 |
2011年 | 432篇 |
2010年 | 283篇 |
2009年 | 47篇 |
2008年 | 63篇 |
2007年 | 38篇 |
2006年 | 43篇 |
2005年 | 27篇 |
2004年 | 35篇 |
2003年 | 30篇 |
2002年 | 21篇 |
2001年 | 5篇 |
2000年 | 13篇 |
1999年 | 9篇 |
1998年 | 10篇 |
1997年 | 8篇 |
1996年 | 11篇 |
1995年 | 8篇 |
1994年 | 8篇 |
1993年 | 8篇 |
1992年 | 6篇 |
1991年 | 2篇 |
1990年 | 3篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1980年 | 1篇 |
1978年 | 1篇 |
1975年 | 1篇 |
1974年 | 2篇 |
排序方式: 共有2313条查询结果,搜索用时 46 毫秒
11.
Amy C. Burrows John Prokop Matthew K. Summers 《The Journal of biological chemistry》2012,287(46):39021-39029
Ubiquitin-mediated proteolysis is a key regulatory process in cell cycle progression. The Skp1-Cul1-F-box (SCF) and anaphase-promoting complex (APC) ubiquitin ligases target numerous components of the cell cycle machinery for destruction. Throughout the cell cycle, these ligases cooperate to maintain precise levels of key regulatory proteins, and indirectly, each other. Recently, we have identified the deubiquitinase USP37 as a regulator of the cell cycle. USP37 expression is cell cycle-regulated, being expressed in late G1 and ubiquitinated by APCCdh1 in early G1. Here we report that in addition to destruction at G1, a major fraction of USP37 is degraded at the G2/M transition, prior to APC substrates and similar to SCFβTrCP substrates. Consistent with this hypothesis, USP37 interacts with components of the SCF in a βTrCP-dependent manner. Interaction with βTrCP and subsequent degradation is phosphorylation-dependent and is mediated by the Polo-like kinase (Plk1). USP37 is stabilized in G2 by depletion of βTrCP as well as chemical or genetic manipulation of Plk1. Similarly, mutation of the phospho-sites abolishes βTrCP binding and renders USP37 resistant to Plk1 activity. Expression of this mutant hinders the G2/M transition. Our data demonstrate that tight regulation of USP37 levels is required for proper cell cycle progression. 相似文献
12.
Yidi Sun Chen Li Shichao Pang Qianlan Yao Luonan Chen Yixue Li Rong Zeng 《基因组蛋白质组与生物信息学报(英文版)》2020,18(5):525-538
The estrogen receptor (ER)-negative breast cancer subtype is aggressive with few treatment options available. To identify specific prognostic factors for ER-negative breast cancer, this study included 705,729 and 1034 breast invasive cancer patients from the Surveillance, Epidemiology, and End Results (SEER) and The Cancer Genome Atlas (TCGA) databases, respectively. To identify key differential kinase–substrate node and edge biomarkers between ER-negative and ER-positive breast cancer patients, we adopted a network-based method using correlation coefficients between molecular pairs in the kinase regulatory network. Integrated analysis of the clinical and molecular data revealed the significant prognostic power of kinase–substrate node and edge features for both subtypes of breast cancer. Two promising kinase–substrate edge features, CSNK1A1–NFATC3 and SRC–OCLN, were identified for more accurate prognostic prediction in ER-negative breast cancer patients. 相似文献
13.
Protein Kinase D3 promotes the cell proliferation by activating the ERK1/c‐MYC axis in breast cancer
Yan Liu Hang Song Shiyi Yu Kuo‐Hsiang Huang Xinxing Ma Yehui Zhou Shuang Yu Jingzhong Zhang Liming Chen 《Journal of cellular and molecular medicine》2020,24(3):2135-2144
Breast cancer is the second leading death cause of cancer death for all women. Previous study suggested that Protein Kinase D3 (PRKD3) was involved in breast cancer progression. In addition, the protein level of PRKD3 in triple‐negative breast adenocarcinoma was higher than that in normal breast tissue. However, the oncogenic mechanisms of PRKD3 in breast cancer is not fully investigated. Multi‐omic data showed that ERK1/c‐MYC axis was identified as a major pivot in PRKD3‐mediated downstream pathways. Our study provided the evidence to support that the PRKD3/ERK1/c‐MYC pathway play an important role in breast cancer progression. We found that knocking out PRKD3 by performing CRISPR/Cas9 genome engineering technology suppressed phosphorylation of both ERK1 and c‐MYC but did not down‐regulate ERK1/2 expression or phosphorylation of ERK2. The inhibition of ERK1 and c‐MYC phosphorylation further led to the lower protein level of c‐MYC and then reduced the expression of the c‐MYC target genes in breast cancer cells. We also found that loss of PRKD3 reduced the rate of the cell proliferation in vitro and tumour growth in vivo, whereas ectopic (over)expression of PRKD3, ERK1 or c‐MYC in the PRKD3‐knockout breast cells reverse the suppression of the cell proliferation and tumour growth. Collectively, our data strongly suggested that PRKD3 likely promote the cell proliferation in the breast cancer cells by activating ERK1‐c‐MYC axis. 相似文献
14.
Genetically encoded fluorescent protein-based kinase biosensors are a central tool for illumination of the kinome. The adaptability and versatility of biosensors have allowed for spatiotemporal observation of real-time kinase activity in living cells and organisms. In this review, we highlight various types of kinase biosensors, along with their burgeoning applications in complex biological systems. Specifically, we focus on kinase activity reporters used in neuronal systems and whole animal settings. Genetically encoded kinase biosensors are key for elucidation of the spatiotemporal regulation of protein kinases, with broader applications beyond the Petri dish. 相似文献
15.
BACKGROUNDTubulins, building blocks of microtubules, are modified substrates of diverse post-translational modifications including phosphorylation, polyglycylation and polyglutamylation. Polyglutamylation of microtubules, catalyzed by enzymes from the tubulin tyrosine ligase-like (TTLL) family, can regulate interactions with molecular motors and other proteins. Due to the diversity and functional importance of microtubule modifications, strict control of the TTLL enzymes has been suggested.AIMTo characterize the interaction between never in mitosis gene A-related kinase 5 (NEK5) and TTLL4 proteins and the effects of TTLL4 phosphorylation.METHODSThe interaction between NEK5 and TTLL4 was identified by yeast two-hybrid screening using the C-terminus of NEK5 (a.a. 260–708) as bait and confirmed by immunoprecipitation. The phosphorylation sites of TTLL4 were identified by mass spectrometry and point mutations were introduced.RESULTSHere, we show that NEK5 interacts with TTLL4 and regulates its polyglutamylation activity. We further show that NEK5 can also interact with TTLL5 and TTLL7. The silencing of NEK5 increases the levels of polyglutamylation of proteins by increasing the activity of TTLL4. The same effects were observed after the expression of the catalytically inactive form of NEK5. This regulation of TTLL4 activity involves its phosphorylation at Y815 and S1136 amino acid residues.CONCLUSIONOur results demonstrate, for the first time, the regulation of TTLL activity through phosphorylation, pointing to NEK5 as a potential effector kinase. We also suggest a general control of tubulin polyglutamylation through NEK family members in human cells. 相似文献
16.
Dimitar B. Nikolov Kai Xu Juha P. Himanen 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(10):2160-2165
The Eph receptors and their ephrin ligands play crucial roles in a large number of cell–cell interaction events, including those associated with axon pathfinding, neuronal cell migration and vasculogenesis. They are also involved in the patterning of most tissues and overall cell positioning in the development of the vertebrate body plan. The Eph/ephrin signaling system manifests several unique features that differentiate it from other receptor tyrosine kinases, including initiation of bi-directional signaling cascades and the existence of ligand and receptor subclasses displaying promiscuous intra-subclass interactions, but very rare inter-subclass interactions. In this review we briefly discuss these features and focus on recent studies of the unique and expansive high-affinity Eph/ephrin assemblies that form at the sites of cell–cell contact and are required for Eph signaling initiation. This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases. 相似文献
17.
目的:腋臭是美容整形外科的常见病,目前发病机制尚不明确,已证实人体大汗腺中的载脂蛋白D(ApoD)在腋臭患者大汗腺中高表达,并且与腋臭的发生密切相关。探明ApoD在大汗腺细胞中的信号转导通路,可以进一步明确其在腋臭发病过程中的作用机制。JNK信号转导通路与多种疾病的发生有关。课题组前期已经做了JNKl对ApoD调控作用的相关研究,证明了在腋臭发病过程中JNK1是通过调控ApoD的转录来上调ApoD的表达。本实验在课题组前期研究基础上,探讨JNKl下游转录因子AP-1是否在JNKl上调ApoD通路中发挥作用。方法:取腋臭志愿者腋区皮肤组织,进行汗腺细胞培养。把汗腺细胞分为5.二氢睾酮处理组、5-二氢睾酮联合姜黄素处理组和空白对照3个组,用姜黄素抑制AP-1的活性,通过Real.timePCR实验方法检测ApoD在姜黄素抑制下的表达变化。结果:在姜黄素的抑制下,ApoD表达明显降低。在体外培养汗腺细胞加入5.二氢睾酮联合姜黄素处理后,ApoD的表达量在mRNA水平低于单独的5-二氢睾酮处理组和正常对照组(P〈0.05)。结论:姜黄素抑制了AP.1的活化导致ApoD的表达降低。在腋臭的发病过程中,JNKl的下游转录因子AP-1对ApoD有明显的上调作用。AP-1可能在JNKl上调ApoD这条通路中扮演了很重要的角色,它可能是JNK1和ApoD的中间转录因子。 相似文献
18.
Hui-Chuan Yu Chen-Si Lin Wei-Tien Tai Chun-Yu Liu Chung-Wai Shiau Kuen-Feng Chen 《The Journal of biological chemistry》2013,288(25):18249-18259
Hepatocellular carcinoma (HCC) is the most common liver cancer and the third-leading cause of cancer death worldwide. Nilotinib is an orally available receptor tyrosine kinase inhibitor approved for chronic myelogenous leukemia. This study investigated the effect of nilotinib on HCC. Nilotinib did not induce cellular apoptosis. Instead, staining with acridine orange and microtubule-associated protein 1 light chain 3 revealed that nilotinib induced autophagy in a dose- and time-dependent manner in HCC cell lines, including PLC5, Huh-7, and Hep3B. Moreover, nilotinib up-regulated the phosphryaltion of AMP-activated kinase (AMPK) and protein phosphatase PP2A inactivation were detected after nilotinib treatment. Up-regulating PP2A activity suppressed nilotinib-induced AMPK phosphorylation and autophagy, suggesting that PP2A mediates the effect of nilotinib on AMPK phosphorylation and autophagy. Our data indicate that nilotinib-induced AMPK activation is mediated by PP2A, and AMPK activation and subsequent autophagy might be a major mechanism of action of nilotinib. Growth of PLC5 tumor xenografts in BALB/c nude mice was inhibited by daily oral treatment with nilotinib. Western blot analysis showed both increased phospho-AMPK expression and decreased PP2A activity in vivo. Together, our results reveal that nilotinib induces autophagy, but not apoptosis in HCC, and that the autophagy-inducing activity is associated with PP2A-regulated AMPK phosphorylation. 相似文献
19.
Christofer Bj?rkelid Terese Bergfors Anand Kumar V. Raichurkar Kakoli Mukherjee Krishnan Malolanarasimhan Balachandra Bandodkar T. Alwyn Jones 《The Journal of biological chemistry》2013,288(25):18260-18270
Mycobacterium tuberculosis, the bacterial causative agent of tuberculosis, currently affects millions of people. The emergence of drug-resistant strains makes development of new antibiotics targeting the bacterium a global health priority. Pantothenate kinase, a key enzyme in the universal biosynthesis of the essential cofactor CoA, was targeted in this study to find new tuberculosis drugs. The biochemical characterizations of two new classes of compounds that inhibit pantothenate kinase from M. tuberculosis are described, along with crystal structures of their enzyme-inhibitor complexes. These represent the first crystal structures of this enzyme with engineered inhibitors. Both classes of compounds bind in the active site of the enzyme, overlapping with the binding sites of the natural substrate and product, pantothenate and phosphopantothenate, respectively. One class of compounds also interferes with binding of the cofactor ATP. The complexes were crystallized in two crystal forms, one of which is in a new space group for this enzyme and diffracts to the highest resolution reported for any pantothenate kinase structure. These two crystal forms allowed, for the first time, modeling of the cofactor-binding loop in both open and closed conformations. The structures also show a binding mode of ATP different from that previously reported for the M. tuberculosis enzyme but similar to that in the pantothenate kinases of other organisms. 相似文献
20.
Katarzyna Malenczyk Magdalena Jazurek Erik Keimpema Cristoforo Silvestri Justyna Janikiewicz Ken Mackie Vincenzo Di Marzo Maria J. Redowicz Tibor Harkany Agnieszka Dobrzyn 《The Journal of biological chemistry》2013,288(45):32685-32699
Endocannabinoid signaling has been implicated in modulating insulin release from β cells of the endocrine pancreas. β Cells express CB1 cannabinoid receptors (CB1Rs), and the enzymatic machinery regulating anandamide and 2-arachidonoylglycerol bioavailability. However, the molecular cascade coupling agonist-induced cannabinoid receptor activation to insulin release remains unknown. By combining molecular pharmacology and genetic tools in INS-1E cells and in vivo, we show that CB1R activation by endocannabinoids (anandamide and 2-arachidonoylglycerol) or synthetic agonists acutely or after prolonged exposure induces insulin hypersecretion. In doing so, CB1Rs recruit Akt/PKB and extracellular signal-regulated kinases 1/2 to phosphorylate focal adhesion kinase (FAK). FAK activation induces the formation of focal adhesion plaques, multimolecular platforms for second-phase insulin release. Inhibition of endocannabinoid synthesis or FAK activity precluded insulin release. We conclude that FAK downstream from CB1Rs mediates endocannabinoid-induced insulin release by allowing cytoskeletal reorganization that is required for the exocytosis of secretory vesicles. These findings suggest a mechanistic link between increased circulating and tissue endocannabinoid levels and hyperinsulinemia in type 2 diabetes. 相似文献