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141.
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143.
Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities 总被引:1,自引:0,他引:1
Stegmeier F Rape M Draviam VM Nalepa G Sowa ME Ang XL McDonald ER Li MZ Hannon GJ Sorger PK Kirschner MW Harper JW Elledge SJ 《Nature》2007,446(7138):876-881
The spindle checkpoint prevents chromosome mis-segregation by delaying sister chromatid separation until all chromosomes have achieved bipolar attachment to the mitotic spindle. Its operation is essential for accurate chromosome segregation, whereas its dysregulation can contribute to birth defects and tumorigenesis. The target of the spindle checkpoint is the anaphase-promoting complex (APC), a ubiquitin ligase that promotes sister chromatid separation and progression to anaphase. Using a short hairpin RNA screen targeting components of the ubiquitin-proteasome pathway in human cells, we identified the deubiquitinating enzyme USP44 (ubiquitin-specific protease 44) as a critical regulator of the spindle checkpoint. USP44 is not required for the initial recognition of unattached kinetochores and the subsequent recruitment of checkpoint components. Instead, it prevents the premature activation of the APC by stabilizing the APC-inhibitory Mad2-Cdc20 complex. USP44 deubiquitinates the APC coactivator Cdc20 both in vitro and in vivo, and thereby directly counteracts the APC-driven disassembly of Mad2-Cdc20 complexes (discussed in an accompanying paper). Our findings suggest that a dynamic balance of ubiquitination by the APC and deubiquitination by USP44 contributes to the generation of the switch-like transition controlling anaphase entry, analogous to the way that phosphorylation and dephosphorylation of Cdk1 by Wee1 and Cdc25 controls entry into mitosis. 相似文献
144.
Koninckx R Daniëls A Windmolders S Carlotti F Mees U Steels P Rummens JL Hendrikx M Hensen K 《Cellular and molecular life sciences : CMLS》2011,68(12):2141-2156
In the past, clinical trials transplanting bone marrow–derived mononuclear cells reported a limited improvement in cardiac
function. Therefore, the search for stem cells leading to more successful stem cell therapies continues. Good candidates are
the so-called cardiac stem cells (CSCs). To date, there is no clear evidence to show if these cells are intrinsic stem cells
from the heart or mobilized cells from bone marrow. In this study we performed a comparative study between human mesenchymal
stem cells (hMSCs), purified c-kit+ CSCs, and cardiosphere-derived cells (CDCs). Our results showed that hMSCs can be discriminated from CSCs by their differentiation
capacity towards adipocytes and osteocytes and the expression of CD140b. On the other hand, cardiac progenitors display a
greater cardiomyogenic differentiation capacity. Despite a different isolation protocol, no distinction could be made between
c-kit+ CSCs and CDCs, indicating that they probably derive from the same precursor or even are the same cells. 相似文献
145.
Feng JQ Ward LM Liu S Lu Y Xie Y Yuan B Yu X Rauch F Davis SI Zhang S Rios H Drezner MK Quarles LD Bonewald LF White KE 《Nature genetics》2006,38(11):1310-1315
The osteocyte, a terminally differentiated cell comprising 90%-95% of all bone cells, may have multiple functions, including acting as a mechanosensor in bone (re)modeling. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (P(i)) homeostasis. Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism. 相似文献
146.
Jung-Eun Park Nak-Kyun Soung Yoshikazu Johmura Young H. Kang Chenzhong Liao Kyung H. Lee Chi Hoon Park Marc C. Nicklaus Kyung S. Lee 《Cellular and molecular life sciences : CMLS》2010,67(12):1957-1970
Members of the polo subfamily of protein kinases have emerged as important regulators in diverse aspects of the cell cycle
and cell proliferation. A large body of evidence suggests that a highly conserved polo-box domain (PBD) present in the C-terminal
non-catalytic region of polo kinases plays a pivotal role in the function of these enzymes. Recent advances in our comprehension
of the mechanisms underlying mammalian polo-like kinase 1 (Plk1)-dependent protein–protein interactions revealed that the
PBD serves as an essential molecular mediator that brings the kinase domain of Plk1 into proximity with its substrates, mainly
through phospho-dependent interactions with its target proteins. In this review, current understanding of the structure and
functions of PBD, mode of PBD-dependent interactions and substrate phosphorylation, and other phospho-independent functions
of PBD are discussed. 相似文献
147.
Caroline Lonez Marc F. Lensink Emilie Kleiren Jean-Marie Vanderwinden Jean-Marie Ruysschaert Michel Vandenbranden 《Cellular and molecular life sciences : CMLS》2010,67(3):483-494
Addition of co-lipids into cationic lipid formulations is considered as promoting cell delivery of DNA by enhancing fusion
processes with cell membranes. Here, by combining FRET and confocal microscopy, we demonstrate that some cationic lipids do
not require a co-lipid to fuse efficiently with cells. These cationic lipids are able to self-organize into bilayers that
are stable enough to form liposomes, while presenting some destabilizing properties reminiscent of the conically shaped fusogenic
co-lipid, DOPE. We therefore analyzed the resident lipid structures in cationic bilayers by molecular dynamics simulations,
clustering the individual lipid structures into populations of similarly shaped molecules, as opposed to the classical approach
of using the static packing parameter to define the lipid shapes. Comparison of fusogenic properties with these lipid populations
suggests that the ratio of cylindrical versus conical lipid populations correlates with the ability to fuse with cell membranes. 相似文献
148.
Aragonés J Schneider M Van Geyte K Fraisl P Dresselaers T Mazzone M Dirkx R Zacchigna S Lemieux H Jeoung NH Lambrechts D Bishop T Lafuste P Diez-Juan A Harten SK Van Noten P De Bock K Willam C Tjwa M Grosfeld A Navet R Moons L Vandendriessche T Deroose C Wijeyekoon B Nuyts J Jordan B Silasi-Mansat R Lupu F Dewerchin M Pugh C Salmon P Mortelmans L Gallez B Gorus F Buyse J Sluse F Harris RA Gnaiger E Hespel P Van Hecke P Schuit F Van Veldhoven P Ratcliffe P Baes M Maxwell P Carmeliet P 《Nature genetics》2008,40(2):170-180
HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress. 相似文献
149.
Prion protein, a misfolded isoform of which is the essential component of the agent of prion diseases, still remains an enigmatic
protein whose physiological functions are at best hypothetical. To gain a better insight into its putative role, many studies
were undertaken to look for molecules that bind prion protein, and have notably identified divalent metal ions, several proteins,
and nucleic acids. At first sight, the diversity of prion protein’s ligands seems of little help to infer a plausible function.
However, the intrinsically disordered property of its N-terminal tail and the potential of the protein to adopt a transmembrane
topology, can both be taken into account to predict its different states during its cellular cycle and its possible functions,
of which the most promising correspond to a general scavenger, a sensor or adaptor in a signaling cascade, and an RNA chaperone.
Received 16 August 2006; received after revision 7 November 2006; accepted 13 December 2006 相似文献
150.
Vermulst M Bielas JH Kujoth GC Ladiges WC Rabinovitch PS Prolla TA Loeb LA 《Nature genetics》2007,39(4):540-543
Whether mitochondrial mutations cause mammalian aging, or are merely correlated with it, is an area of intense debate. Here, we use a new, highly sensitive assay to redefine the relationship between mitochondrial mutations and age. We measured the in vivo rate of change of the mitochondrial genome at a single-base pair level in mice, and we demonstrate that the mutation frequency in mouse mitochondria is more than ten times lower than previously reported. Although we observed an 11-fold increase in mitochondrial point mutations with age, we report that a mitochondrial mutator mouse was able to sustain a 500-fold higher mutation burden than normal mice, without any obvious features of rapidly accelerated aging. Thus, our results strongly indicate that mitochondrial mutations do not limit the lifespan of wild-type mice. 相似文献