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481.
Nobuya Kurabe Satoko Arai Akemi Nishijima Naoto Kubota Futoshi Suizu Mayumi Mori Jun Kurokawa Miki Kondo-Miyazaki Tomohiro Ide Kouji Murakami Katsuhisa Miyake Kohjiro Ueki Hisashi Koga Yutaka Yatomi Fumio Tashiro Masayuki Noguchi Takashi Kadowaki Toru Miyazaki 《The Journal of biological chemistry》2009,284(8):5050-5055
Cell cycle regulation and biochemical responses upon nutrients and growth
factors are the major regulatory mechanisms for cell sizing in mammals.
Recently, we identified that the death effector domain-containing DEDD impedes
mitotic progression by inhibiting Cdk1 (cyclin-dependent kinase 1) and thus
maintains an increase of cell size during the mitotic phase. Here we found
that DEDD also associates with S6 kinase 1 (S6K1), downstream of
phosphatidylinositol 3-kinase, and supports its activity by preventing
inhibitory phosphorylation of S6K1 brought about by Cdk1 during the mitotic
phase. DEDD-/- cells showed reduced S6K1 activity, consistently
demonstrating decreased levels in activating phosphorylation at the Thr-389
site. In addition, levels of Cdk1-dependent inhibitory phosphorylation at the
C terminus of S6K1 were enhanced in DEDD-/- cells and tissues.
Consequently, as in S6K1-/- mice, the insulin mass within
pancreatic islets was reduced in DEDD-/- mice, resulting in glucose
intolerance. These findings suggest a novel cell sizing mechanism achieved by
DEDD through the maintenance of S6K1 activity prior to cell division. Our
results also suggest that DEDD may harbor important roles in glucose
homeostasis and that its deficiency might be involved in the pathogenesis of
type 2 diabetes mellitus.Cell size is closely related to specialized cell function and to the
specific patterning of tissues in the body. Cell sizing is regulated mainly by
two mechanisms: cell cycle control and the biochemical response to nutrients
and/or growth factors
(1–5).
During cell cycle progression, both the G1 (which is believed to be
dominant) and the G2 periods are important for cells to increase
their volume
(6–9).
In addition, we recently provided evidence that the mitotic period (M phase)
also influences cell size, through analysis of DEDD-deficient mice
(10,
11). The DEDD molecule was
initially described as a member of the death effector domain
(DED)2-containing
protein family (12). Although
the absence of DEDD did not apparently influence progression of apoptosis
(10), we found that during
mitosis, DEDD is associated with Cdk1-cyclin B1 and that it decreases the
kinase activity of Cdk1. This response impedes the Cdk1-dependent mitotic
program to shut off synthesis of ribosomal RNA (rRNA) and protein and is
consequently useful in gaining sufficient cell growth prior to cell division.
Depletion of DEDD consistently results in a shortened mitotic duration and an
overall reduction in the amount of cellular rRNA and protein and, furthermore,
in cell and body size (10,
11).Of the biochemical responses responsible for cell sizing, the signaling
cascade involving phosphatydilinositol 3-kinase (PI3K) and its downstream
target of rapamycin (TOR) is most crucial
(13–15).
In mammals, upon stimulation by growth factors, including insulin, the
mammalian TOR (mTOR) cooperates with PI3K-dependent effectors to activate
S6K1, thereby phosphorylating the 40 S ribosomal protein S6, and subsequently
enhances translation of the 5′-terminal oligopyrimidine sequences that
encode components of the translational machinery. This reaction increases the
number of ribosomes and the efficacy of protein synthesis, thus critically
promoting cell growth
(16–18).
Therefore, mice deficient for S6K1 (S6K1-/-) had reduced cell and
body size
(19–23).
This effect also involves S6K1 in maintenance of glucose tolerance. S6K1
significantly supports the size of insulin-producing β cells within
pancreatic Langerhans islets
(24,
25). Thus, in
S6K1-/- mice, the insulin mass was diminished, which resulted in
ineffective secretion of insulin upon glucose administration
(21,
23).The activation of S6K1 proceeds through chronological phosphorylation at
various residues, toward the crucial phosphorylation of Thr-389, present
within the linker domain between the catalytic domain and the carboxyl tail,
to obtain maximal enzymatic activity
(26). Interestingly,
phosphorylation at several Ser/Thr residues within the C-terminal
autoinhibitory tail appears to either activate or inhibit S6K1, depending on
the cell cycle phase. Shah et al.
(27) demonstrated that
phosphorylation of those residues (featured by the Thr-421/Ser-424 site)
during mitosis pursued by Cdk1 inactivates S6K1 to terminate protein synthesis
prior to cell division (28). A
recent report by Schmidt et al.
(29) demonstrating that
phosphorylation of Thr-421/Ser-424 is specifically increased during the
G2/M phase may also support the finding, whereas during the
G1 phase, there is consensus that the phosphorylation at the
autoinhibitory domain is requisite for S6K1 activation
(26), as also recently
demonstrated by Hou et al.
(30), where the Cdk5
phosphorylates the Ser-411 site, leading to activation of S6K1. In contrast to
such inhibitory regulation of S6K1 during mitosis, however, a recent report by
Boyer et al. (31)
sharply demonstrated that the activity of S6K1 peaks at mitosis, suggesting
that S6K1 may also have some roles during the mitotic phase. If so, how its
activity is supported against the inhibitory regulation caused by Cdk1 remains
an open question.Hence, the two observations above that both DEDD-/- and
S6K1-/- situations decrease the efficacy of ribosome and protein
synthesis, resulting in smaller cell and body size, and that mitotic Cdk1 has
a functional interaction with both S6K1 and DEDD led us here to assess a
possible role of DEDD in the context of the functional regulation of S6K1. 相似文献
482.
483.
Castro-Guerrero N Sinha PK Torres-Bacete J Matsuno-Yagi A Yagi T 《Biochemistry》2010,49(47):10072-10080
The prokaryotic proton-translocating NADH-quinone oxidoreductase (NDH-1) is an L-shaped membrane-bound enzyme that contains 14 subunits (NuoA-NuoN or Nqo1-Nqo14). All subunits have their counterparts in the eukaryotic enzyme (complex I). NDH-1 consists of two domains: the peripheral arm (NuoB, -C, -D, -E, -F, -G, and -I) and the membrane arm (NuoA, -H, -J, -K, -L, -M, and -N). In Escherichia coli NDH-1, the hydrophilic subunits NuoC/Nqo5/30k and NuoD/Nqo4/49k are fused together in a single polypeptide as the NuoCD subunit. The NuoCD subunit is the only subunit that does not bear a cofactor in the peripheral arm. While some roles for inhibitor and quinone association have been reported for the NuoD segment, structural and functional roles of the NuoC segment remain mostly elusive. In this work, 14 highly conserved residues of the NuoC segment were mutated and 21 mutants were constructed using the chromosomal gene manipulation technique. From the enzymatic assays and immunochemical and blue-native gel analyses, it was found that residues Glu-138, Glu-140, and Asp-143 that are thought to be in the third α-helix are absolutely required for the energy-transducing NDH-1 activities and the assembly of the whole enzyme. Together with available information for the hydrophobic subunits, we propose that Glu-138, Glu-140, and Asp-143 of the NuoC segment may have a pivotal role in the structural stability of NDH-1. 相似文献
484.
Jun Li Hidetoshi Nara Mizanur Rahman Farha Matin Juliana Akemi Araki Hironobu Asao 《Cytokine》2010,49(2):221-228
Janus kinase 3-severe combined immunodeficiency (JAK3-SCID) is an autosomal recessive immunodeficiency disease caused by various mutations in the JAK3 gene. Typical JAK3-SCID is characterized by a phenotype in which B cells are present but T and NK cells are not, the T?B+NK? phenotype, and by impaired signaling through cytokine receptors that use the common gamma chain (γc) subunit. An atypical JAK3-SCID case carrying a single glutamate to glycine substitution mutation (E481G) in the JH3 domain of one JAK3 allele, and a deletion mutation (del482-596) in the JH3 and JH2 domains of the other allele was reported previously. Although this patient had CD4+ T cells and NK cells unlike typical cases, the CD4+ T cells were functionally impaired. We report here that the JAK3-E481G mutant transduced IL-2-, IL-4-, IL-15-, and IL-21-induced signals as efficiently as wild-type JAK3. However, this mutant failed to respond to IL-7 by phosphorylating JAK1, JAK3, or STAT5. The other mutant JAK3, JAK3-del482-596, was non-functional. Thus, an impaired IL-7 signal may cause SCID and compromise T-cell differentiation, even if the IL-15 signal is preserved and supports NK-cell development, as in this patient. 相似文献
485.
Colado Simão AN Suzukawa AA Casado MF Oliveira RD Guarnier FA Cecchini R 《Life sciences》2006,78(11):1202-1210
The pre-hemolytic mechanism induced by free radicals initiated from water-soluble 2,2'-azobis (2-amidinopropane) hydrochloride (AAPH) and its reversal by genistein was investigated in human erythrocytes. The time course of K+ efflux compared to the occurrence of hemolysis suggests that AAPH-induced hemolysis occurs indirectly via pore formation and band 3 oxidation as expected. However, genistein inhibited hemolysis, LDH release and membrane protein oxidation but not K+ efflux. This indicated that erythrocyte protein oxidation possibly in the hydrophobic core plays a significant role in the membrane pre-hemolytic damage. Chemiluminescence (CL) analysis carried out in non-lysed erythrocytes treated with AAPH showed a dramatic increase in CL indicating both reduced levels of antioxidants and increased membrane lipid peroxide. The V0 value was also increased up to 6 times, denoting a high degree of membrane peroxidation very early in erythrocyte membrane damage. The whole process was inhibited by genistein in a dose-dependent manner. These results indicate that the genistein inhibited both hemolysis and pre-hemolytic damage and also hindered membrane lipid peroxide formation and protein oxidation. In addition, it is suggested that pre-hemolytic damage is mediated mainly by the oxidation of both phospholipid and protein located in the deeper hydrophobic region of the membrane. 相似文献
486.
Suzuki T Zhao YL Nadai M Naruhashi K Shimizu A Takagi K Takagi K Hasegawa T 《Life sciences》2006,79(5):455-461
To clarify whether gender-related differences exist in the expression and function of hepatic P-glycoprotein- and/or multidrug resistance-associated protein (Mrp2), we measured the hepatobiliary excretion of doxorubicin and their protein levels in male and female Sprague-Dawley rats. When rats received a single intravenous injection of doxorubicin (5 mg/kg), a delay in the disappearance of doxorubicin from plasma was observed in male rats. When rats received a constant-rate infusion of doxorubicin, no significant gender-related differences in the apparent biliary clearance of doxorubicin based on the steady state plasma concentrations were observed between male and female rats. However, the net biliary clearance of doxorubicin based on the liver concentration, which represents the actual function of P-glycoprotein and/or Mrp2, was higher in female rats than in male rats. These results suggest that the actual function of the hepatobiliary transport of doxorubicin is greater in female than in male rats. Western blot analysis revealed that the expression of P-glycoprotein and Mrp2 in the liver of female rats was significantly higher than in male rats, similar to results of hepatobiliary excretion experiments. The expression of hepatic cytochrome P450 (CYP) 2B1, which is involved in the metabolism of doxorubicin, was significantly higher in male than in female rats. By pretreatment with testosterone (10 mg/day for 7 days), the actual biliary clearance of doxorubicin in female rats was nearly that of male rats. The protein levels of P-glycoprotein and Mrp2 in female rats were also lowered by treatment with testosterone so as to be nearer those in male rats. These results suggest that gender-related differences exist in P-glycoprotein- and Mrp2-mediated hepatobiliary transport and that these two transporters may be regulated by sex hormones. 相似文献
487.
488.
Essential role of IkappaB kinase alpha in thymic organogenesis required for the establishment of self-tolerance 总被引:1,自引:0,他引:1
Kinoshita D Hirota F Kaisho T Kasai M Izumi K Bando Y Mouri Y Matsushima A Niki S Han H Oshikawa K Kuroda N Maegawa M Irahara M Takeda K Akira S Matsumoto M 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(7):3995-4002
IkappaB kinase (IKK) alpha exhibits diverse biological activities through protein kinase-dependent and -independent functions, the former mediated predominantly through a noncanonical NF-kappaB activation pathway. The in vivo function of IKKalpha, however, still remains elusive. Because a natural strain of mice with mutant NF-kappaB-inducing kinase (NIK) manifests autoimmunity as a result of disorganized thymic structure with abnormal expression of Rel proteins in the thymic stroma, we speculated that the NIK-IKKalpha axis might constitute an essential step in the thymic organogenesis that is required for the establishment of self-tolerance. An autoimmune disease phenotype was induced in athymic nude mice by grafting embryonic thymus from IKKalpha-deficient mice. The thymic microenvironment that caused autoimmunity in an IKKalpha-dependent manner was associated with defective processing of NF-kappaB2, resulting in the impaired development of thymic epithelial cells. Thus, our results demonstrate a novel function for IKKalpha in thymic organogenesis for the establishment of central tolerance that depends on its protein kinase activity in cooperation with NIK. 相似文献
489.
J. F. van den Bosch P. L. Oe P. Postma J. de Graaff D. M. MacLaren W. H. Jansen P. A. M. Guinée 《Antonie van Leeuwenhoek》1980,46(4):321-329
E. coli strains were isolated from urine specimens of hospitalised patients with acute pyelonephritis, acute cystitis or asymptomatic bacteriuria (ABU), and tested for virulence in an experimental mouse model. Of 12 pyelonephritisstrains 11 were shown to be virulent and 1 avirulent; of 12 cystitis-strains 4 were virulent and 8 avirulent; of 12 ABU-strains 5 were virulent and 7 avirulent. It is concluded that, while no difference in virulence was found between cystitis-and ABU-strains, pyelonephritis-strains were more often virulent than cystitis-and ABU-strains.No associations could be shown between virulence of the isolated strains and the presence of antibody-coated bacteria in the urine. Common urinary O types were not more often virulent than other O types. No relationship was seen between virulence and the presence of K antigen or the presence of particular K types. 相似文献
490.
Bovine oocytes surrounded with compact cumulus cells were cultured for 20 to 22 hours (38.5 degrees C, 5% CO(2)) in modified TCM-199 medium supplemented with 5% superovulated cow serum (SCS) and inseminated by in vitro capacitated spermatozoa. Day 7 to 8 embryos were equilibrated for 10 minutes in 1.3 M methyl cellosolve (MC), 1.1 M diethylene glycol (DEG), 1.8 M ethylene glycol (EG), 1.6 M propylene glycol (PG) and 1.1 M 1, 3-butylene glycol (BG) solutions. They were then loaded into 0.25-ml straws, placed into an alcohol bath freezer at 0 degrees C, cooled from 0 degrees C to -6 degrees C at -1 degrees C/minute, seeded, held for 10 minutes, and cooled again at -0.3 degrees C or -0.5 degrees C/minute to -30 degrees C. Straws were then plunged and stored in liquid nitrogen. After thawing in 30 degrees C water, the embryos were rehydrated in TCM-199 medium and then cultured for 48 hours in TCM-199 plus 5% SCS. Embryos were considered viable if they progressed to later developmental stages with good morphology. Some of the embryos frozen in each cryoprotectant were thawed and transferred nonsurgically without removing the cryoprotectant. Hatched embryos survived freezing and one-step dilution as follows: EG (50.0%), MC (53.6%), DEG (56.9%), PG (58.0%) and BG (11.5%). The survival rate of embryos cooled at -0.3 degrees C vs -0.5 degrees C/minute was not significantly different (P>0.05), however, blastocysts hatched most often (P<0.01) in vitro when cooled at a rate of -0.3 degrees C/minute (64.6%, 31 48 ) than at -0.5 degrees C/minute (22.6%, 12 53 ). Pregnancy rates resulting from embryos frozen in the different cryoprotectants were as follows: MC (48%, 10 21 ); DEG (30%, 3 10 ); EG (74%, 20 27 ); and PG (40%, 4 10 ). These results indicate that MC, DEG, EG and PG have utility as cryoprotectants for the freezing and thawing of IVF bovine embryos. 相似文献