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The cell division cycle 25A (Cdc25A) phosphatase is a critical regulator of cell cycle progression under normal conditions and after stress. Stress-induced degradation of Cdc25A has been proposed as a major way of delaying cell cycle progression. In vitro studies pointed toward serine 123 as a key site in regulation of Cdc25A stability after exposure to ionizing radiation (IR). To address the role of this phosphorylation site in vivo, we generated a knock-in mouse in which alanine was substituted for serine 123. The Cdc25 S123A knock-in mice appeared normal, and, unexpectedly, cells derived from them exhibited unperturbed cell cycle and DNA damage responses. In turn, we found that Cdc25A was present in centrosomes and that Cdc25A levels were not reduced after IR in knock-in cells. This resulted in centrosome amplification due to lack of induction of Cdk2 inhibitory phosphorylation after IR specifically in centrosomes. Further, Cdc25A knock-in animals appeared sensitive to IR-induced carcinogenesis. Our findings indicate that Cdc25A S123 phosphorylation is crucial for coupling centrosome duplication to DNA replication cycles after DNA damage and therefore is likely to play a role in the regulation of tumorigenesis. 相似文献
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Neonatal FcR expression in bone marrow-derived cells functions to protect serum IgG from catabolism 总被引:1,自引:0,他引:1
Akilesh S Christianson GJ Roopenian DC Shaw AS 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(7):4580-4588
The neonatal FcR (FcRn) is a receptor that protects IgG from catabolism and is important in maintaining high serum Ab levels. A major site of expression of FcRn is vascular endothelial cells where FcRn functions to extend the serum persistence of IgG by recycling internalized IgG back to the surface. Because FcRn is expressed in other tissues, it is unclear whether endothelial cells are the only site of IgG protection. In this study, we used FcRn-deficient mice and specific antiserum to determine the tissue distribution of FcRn in the adult mouse. In addition to its expression in the vascular endothelium of several organs, we found FcRn to be highly expressed in bone marrow-derived cells and professional APCs in different tissues. Experiments using bone marrow chimeras showed that FcRn expression in these cells acted to significantly extend the half-life of serum IgG indicating that in addition to the vascular endothelium, bone marrow-derived phagocytic cells are a major site of IgG homeostasis. 相似文献
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Gregory J Christianson Victor Z Sun Shreeram Akilesh Emanuele Pesavento Gabriele Proetzel Derry C Roopenian 《MABS-AUSTIN》2012,4(2):208-216
The MHC class I-like Fc receptor (FcRn) is an intracellular trafficking Fc receptor that is uniquely responsible for the extended serum half-life of antibodies of the IgG subclass and their ability to transport across cellular barriers. By performing these functions, FcRn affects numerous facets of antibody biology and pathobiology. Its critical role in controlling IgG pharmacokinetics has been leveraged for the design of therapeutic antibodies and related biologics. FcRn also traffics serum albumin and is responsible for the enhanced pharmacokinetic properties of albumin-conjugated therapeutics. The understanding of FcRn and its therapeutic applications has been limited by a paucity of reliable serological reagents against human FcRn. Here, we describe the properties of a new panel of highly specific monoclonal antibodies (mAbs) directed against human FcRn with diverse epitope specificities. We show that this antibody panel can be used to study the tissue expression pattern of human FcRn, to selectively block IgG and serum albumin binding to human FcRn in vitro and to inhibit FcRn function in vivo. This mAb panel provides a powerful resource for probing the biology of human FcRn and for the evaluation of therapeutic FcRn blockade strategies.Key words: FcRn, IgG, monoclonal antibody, albumin, therapy 相似文献
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The MHC class I-like IgG receptor controls perinatal IgG transport,IgG homeostasis,and fate of IgG-Fc-coupled drugs 总被引:1,自引:0,他引:1
Roopenian DC Christianson GJ Sproule TJ Brown AC Akilesh S Jung N Petkova S Avanessian L Choi EY Shaffer DJ Eden PA Anderson CL 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(7):3528-3533
Abs of the IgG isotype are efficiently transported from mother to neonate and have an extended serum t(1/2) compared with Abs of other isotypes. Circumstantial evidence suggests that the MHC class I-related protein, the neonatal FcR (FcRn), is the FcR responsible for both in vivo functions. To understand the phenotypes imposed by FcRn, we produced and analyzed mice with a defective FcRn gene. The results provide direct evidence that perinatal IgG transport and protection of IgG from catabolism are mediated by FcRn, and that the latter function is key to IgG homeostasis, essential for generating a potent IgG response to foreign Ags, and the basis of enhanced efficacy of Fc-IgG-based therapeutics. FcRn is therefore a promising therapeutic target for enhancing protective humoral immunity, treating autoimmune disease, and improving drug efficacy. 相似文献
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The neonatal Fc receptor for IgG (FcRn) has been well characterized in the transfer of passive humoral immunity from a mother to her fetus. In addition, throughout life, FcRn protects IgG from degradation, thereby explaining the long half-life of this class of antibody in the serum. In recent years, it has become clear that FcRn is expressed in various sites in adults, where its potential function is now beginning to emerge. In addition, recent studies have examined the interaction between FcRn and the Fc portion of IgG with the aim of either improving the serum half-life of therapeutic monoclonal antibodies or reducing the half-life of pathogenic antibodies. This Review summarizes these two areas of FcRn biology. 相似文献
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Crissy Dudgeon Sathyavageeswaran Shreeram Kan Tanoue Sharlyn J Mazur Ahmed Sayadi Robert C Robinson Ettore Appella Dmitry V Bulavin 《Cell cycle (Georgetown, Tex.)》2013,12(16):2656-2664
The Wip1 phosphatase is an oncogene that is overexpressed in a variety of primary human cancers. We were interested in identifying genetic variants that could change Wip1 activity. We identified 3 missense SNPs of the human Wip1 phosphatase, L120F, P322Q, and I496V confer a dominant-negative phenotype. On the other hand, in primary human cancers, PPM1D mutations commonly result in a gain-of-function phenotype, leading us to identify a hot-spot truncating mutation at position 525. Surprisingly, we also found a significant number of loss-of-function mutations of PPM1D in primary human cancers, both in the phosphatase domain and in the C terminus. Thus, PPM1D has evolved to generate genetic variants with lower activity, potentially providing a better fitness for the organism through suppression of multiple diseases. In cancer, however, the situation is more complex, and the presence of both activating and inhibiting mutations requires further investigation to understand their contribution to tumorigenesis. 相似文献