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941.
The relationships between the distribution of the native auxin indole-3-acetic acid (IAA) and tropisms in the epicotyl of red light-grown pea (Pisum sativum L.) seedlings have been investigated. The distribution measurement was made in a defined zone of the third internode, using (3)H-IAA applied from the plumule as a tracer. The tropisms investigated were gravitropism, pulse-induced phototropism, and time-dependent phototropism. The investigation was extended to the phase of autostraightening (autotropism) that followed gravitropic curvature. It was found that IAA is asymmetrically distributed between the two halves of the zone, with a greater IAA level occurring on the convex side, at early stages of gravitropic and phototropic curvatures. This asymmetry was found in epidermal peels and, except for one case (pulse-induced phototropism), no asymmetry was detected in whole tissues. It was concluded, in support of earlier results, that auxin asymmetry mediates gravitropism and phototropism and that the epidermis or peripheral cell layers play an important role in the establishment of auxin asymmetry in pea epicotyls. During autostraightening, which results from a reversal of growth asymmetry, the extent of IAA asymmetry was reduced, but its direction was not reversed. This result demonstrated that autostraightening is not regulated through auxin distribution. In this study, the growth on either side of the investigated zone was also measured. In some cases, the measured IAA distribution could not adequately explain the local growth rate, necessitating further detailed investigation. 相似文献
942.
Tsuruma K Nakagawa T Morimoto N Minami M Hara H Uehara T Nomura Y 《The Journal of biological chemistry》2006,281(16):11397-11404
Caspases are divided into two classes: initiator caspases, which include caspase-8 and -9 and possess long prodomains, and effector caspases, which include caspase-3 and -7 and possess short prodomains. Recently, we demonstrated that glucocorticoid modulatory element-binding protein 1 (GMEB1) interacts with the prodomain of procaspase-2, thereby disrupting its autoactivation and the induction of apoptosis. Here we show that GMEB1 is also capable of binding to procaspase-8 and -9. GMEB1 attenuated the Fas-mediated activation of these caspases and the subsequent apoptosis. The knockdown of endogenous GMEB1 using RNA interference revealed that cells with decreased GMEB1 expression are more sensitive to stress and undergo accelerated apoptosis. Transgenic mice expressing a neurospecific GMEB1 had smaller cerebral infarcts and less brain swelling than wild-type mice in response to transient focal ischemia. These results suggest that GMEB1 is an endogenous regulator that selectively binds to initiator procaspases and inhibits caspase-induced apoptosis. 相似文献
943.
Koike D Obinata H Yamamoto A Takeda S Komori H Nara F Izumi T Haga T 《Journal of biochemistry》2006,139(3):543-549
While screening genes encoding G protein-coupled receptors (GPCRs) in the human genome, we and other groups have identified a GPCR named hGPCR48 as a high affinity receptor for 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), which is arachidonic acid metabolite and an endogenous chemoattractant for granulocytes. Using Chinese hamster ovary (CHO) cells stably expressing hGPCR48, we show here that activation of the receptor causes the chemotaxis of the cells toward 5-oxo-ETE. We also show that the chemotaxis of human granulocytes toward 5-oxo-ETE is inhibited by pretreatment with anti-hGPCR48 antibodies, indicating that hGPCR48 is an endogenous receptor responsible for chemotaxis of granulocytes toward 5-oxo-ETE. In addition, we show that the chemotaxis of CHO cells expressing hGPCR48 is suppressed by pretreatment with pertussis toxin, and enhanced by overexpression of the carboxy terminal peptides of Galpha (12/13) subunits or a regulator of the G protein signaling domain of p115RhoGEF, both of which are known to suppress G(12/13)-dependent signaling pathways. These results indicate that hGPCR48 couples with G(i/o) and G(12/13) proteins, which then initiate or attenuate the chemotaxis of the cells toward 5-oxo-ETE, respectively. 相似文献
944.
Toshihiro Sakamoto Minoru Moriya Yuji Haga Toshiyuki Takahashi Takunobu Shibata Osamu Okamoto Katsumasa Nonoshita Hidefumi Kitazawa Masayasu Hidaka Akira Gomori Hisashi Iwaasa Akane Ishihara Akio Kanatani Takehiro Fukami Ying-Duo Gao Douglas J. MacNeil Lihu Yang 《Bioorganic & medicinal chemistry letters》2009,19(6):1564-1568
A series of spiroindoline-3,4′-piperidine derivatives were synthesized and evaluated for their binding affinities and antagonistic activities at Y5 receptors. Potent Y5 antagonists were tested for their oral bioavailabilities and brain penetration in rats. Some of the antagonists showed good oral bioavailability and/or good brain penetration. In particular, compound 6e was orally bioavailable and brain penetrant, and oral administration of 6e inhibited bPP-induced food intake in rats with a minimum effective dose of 10 mg/kg. 相似文献
945.
Yuji Haga Toshihiro Sakamoto Takunobu Shibata Katsumasa Nonoshita Makoto Ishikawa Takuya Suga Hirobumi Takahashi Toshiyuki Takahashi Hidekazu Takahashi Makoto Ando Takashi Murai Akira Gomori Zenjun Oda Hidefumi Kitazawa Yuko Mitobe Maki Kanesaka Tomoyuki Ohe Hisashi Iwaasa Yasuyuki Ishii Akane Ishihara Takehiro Fukami 《Bioorganic & medicinal chemistry》2009,17(19):6971-6982
A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1 mg/kg. This compound was selected for proof-of-concept studies in human clinical trials. 相似文献
946.
Nobuchika Suzuki Kouhei Tsumoto Nicole Hajicek Kenji Daigo Reiko Tokita Shiro Minami Tatsuhiko Kodama Takao Hamakubo Tohru Kozasa 《The Journal of biological chemistry》2009,284(8):5000-5009
The transient protein-protein interactions induced by guanine
nucleotide-dependent conformational changes of G proteins play central roles
in G protein-coupled receptor-mediated signaling systems. Leukemia-associated
RhoGEF (LARG), a guanine nucleotide exchange factor for Rho, contains an RGS
homology (RH) domain and Dbl homology/pleckstrin homology (DH/PH) domains and
acts both as a GTPase-activating protein (GAP) and an effector for
Gα13. However, the molecular mechanism of LARG activation
upon Gα13 binding is not yet well understood. In this study,
we analyzed the Gα13-LARG interaction using cellular and
biochemical methods, including a surface plasmon resonance (SPR) analysis. The
results obtained using various LARG fragments demonstrated that active
Gα13 interacts with LARG through the RH domain, DH/PH
domains, and C-terminal region. However, an alanine substitution at the RH
domain contact position in Gα13 resulted in a large decrease
in affinity. Thermodynamic analysis revealed that binding of
Gα13 proceeds with a large negative heat capacity change
(ΔCp°), accompanied by a positive entropy change
(ΔS°). These results likely indicate that the binding of
Gα13 with the RH domain triggers conformational
rearrangements between Gα13 and LARG burying an exposed
hydrophobic surface to create a large complementary interface, which
facilitates complex formation through both GAP and effector interfaces, and
activates the RhoGEF. We propose that LARG activation is regulated by an
induced-fit mechanism through the GAP interface of Gα13.Heterotrimeric G
proteins3 serve as key
molecular switches to transduce a large array of extracellular signals into
cells by actively alternating their conformations between GDP-bound inactive
and GTP-bound active forms. In the current model, the ligand-activated G
protein-coupled receptors (GPCRs) catalyze the exchange of GDP for GTP on
Gα subunits (1). Upon
activation, three switch regions in the Gα subunit undergo significant
conformational changes, followed by dissociation of the GTP-bound Gα
subunit from the Gβγ subunits. Both Gα-GTP and free
Gβγ interact with diverse downstream effectors to transmit
intracellular signals. The Gα subunit hydrolyzes bound GTP to GDP by its
intrinsic GTPase activity. This deactivation process is further accelerated by
GTPase-activating proteins (GAPs) such as regulator of G protein signaling
(RGS) proteins (2,
3). Gα-GDP dissociates
from effectors and re-associates with Gβγ to terminate the
signal.Although this model explains the basic concept of G protein signaling, the
molecular dynamics of interactions among GPCR, G protein, RGS protein, and
effector during the signaling process is not well understood. It has been
suggested that the GPCR signals are integrated into the intracellular
signaling network at the level of G proteins
(4). Accumulating evidence
suggests that the Gα subunit acts as the core of the signaling complex
at the membrane, which is formed through the transient protein-protein
interactions of multiple signaling components
(5,
6). Thus, the quantitative
analysis of the dynamic molecular interactions in the GPCR signaling complex
will be crucial to understanding various cellular processes.Gα12 and Gα13 subunits have been
demonstrated to regulate the activity of Rho GTPase through RhoGEFs, which
contain an N-terminal RGS homology domain (RH-RhoGEFs)
(7–10).
RH-RhoGEFs, which consist of p115RhoGEF/Lsc, PDZ-Rho-GEF/GTRAP48, and LARG in
mammalian species, directly link the activation of GPCRs by extracellular
ligands to the regulation of Rho activity in cells
(10–14).
All three RH-RhoGEFs contain an N-terminal RH domain, which specifically
recognizes the active form of Gα12 or Gα13
and central DH/PH domains characteristic of GEFs for Rho GTPases. It has been
demonstrated in vitro that LARG and p115RhoGEF serve as specific GAPs
for Gα12/13 through their RH domains and also as their
effectors to regulate Rho GTPase activation
(11–13).
A structural study has demonstrated that the interface of the RH domain of
p115RhoGEFs and a Gα13/i1 chimera is different from that of
the RGS domain of RGS4 and Gαi1
(7). The N-terminal small
element in the RH domain, which is required for GAP activity toward
Gα13, contacts the switch regions and the helical domain of
the Gα13/i1 chimera. The core module of the p115RhoGEF RH
domain binds to the region of Gα13/i1, which is
conventionally used for effector binding. These results suggest roles for the
RH domain in the stimulation of GEF activity by Gα13 in
addition to GAP activity. On the other hand, several studies have also
indicated that regions outside of RH domain of RH-RhoGEFs, particularly the
DH/PH domains, interact directly with activated Gα13
(11,
14,
15). In addition, we have
demonstrated recently that p115RhoGEF interacts with distinct surfaces of
Gα13 for the GAP reaction or GEF activity regulation
(16). However, the molecular
mechanism of LARG activation upon Gα13 binding is not clearly
understood.In this study, we have developed a quantitative method for the kinetic and
thermodynamic analysis of Gα13-effector interaction using
surface plasmon resonance (SPR) with sensor chips on which
Gα13 was immobilized. We examined the kinetics and
thermodynamics of the Gα13-LARG interaction and assessed LARG
activation using both in vitro and cell-based approaches. We present
evidence that, in addition to the interaction with the RH domain, the DH/PH
domains and C-terminal region of LARG also interact with Gα13
to form the high affinity Gα13-LARG complex and activate
RhoGEF activity. We further propose that LARG adopts the active conformation
using an induced-fit mechanism through association with the GAP interface of
Gα13. A similar mechanism may also be used with other
Gα-effector interactions. 相似文献
947.
Amanda Mikels Yasuhiro Minami Roel Nusse 《The Journal of biological chemistry》2009,284(44):30167-30176
948.
Sakai T Ohtsubo S Minami T Terayama M 《Bioscience, biotechnology, and biochemistry》2006,70(4):1006-1008
Skipjack samples were prepared using two different killing methods, namely, struggling death in iced sea water (control) and instant death by mechanical bleeding. The hemoglobin content in the bled muscles was significantly lower than that in the control. 4-Hydroxyhexenal content in the bled muscles was significantly lower than that in the control over 2 d of storage at 0 degrees C. 相似文献
949.
Wip1 phosphatase modulates ATM-dependent signaling pathways 总被引:3,自引:0,他引:3
Shreeram S Demidov ON Hee WK Yamaguchi H Onishi N Kek C Timofeev ON Dudgeon C Fornace AJ Anderson CW Minami Y Appella E Bulavin DV 《Molecular cell》2006,23(5):757-764
Deletion of Ppm1d, the gene encoding the Wip1 phosphatase, renders cells resistant to transformation and mice resistant to tumor development. Here, we report that deficiency of Wip1 resulted in activation of the ataxia-telangiectasia mutated (ATM) kinase. In turn, overexpression of Wip1 was sufficient to reduce activation of the ATM-dependent signaling cascade after DNA damage. Wip1 dephosphorylated ATM Ser1981, a site critical for ATM monomerization and activation, and was critical for resetting ATM phosphorylation as cells repaired damaged DNA. We propose that the Wip1 phosphatase is an integral component of an ATM-dependent signaling pathway. 相似文献
950.
Jackson TA Haga CL Ehrhardt GR Davis RS Cooper MD 《Journal of immunology (Baltimore, Md. : 1950)》2010,185(12):7405-7412
FcR-like (FCRL) 2 is a transmembrane protein with immunomodulatory potential that is preferentially expressed by memory B cells in humans. It has two consensus ITIMs in addition to a putative ITAM sequence in its cytoplasmic domain. We have confirmed the cellular distribution of FCRL2 and analyzed its functional potential to show that coligation with the BCR leads to tyrosine phosphorylation of its ITIM motifs and subsequent Src homology region 2 domain-containing phosphatase-1 recruitment to facilitate inhibition of BCR signaling. Mutational analysis indicates that the tyrosine residues in both inhibitory motifs of FCRL2 are required for complete inhibition of BCR signaling, whereas tyrosines in the putative activation motif are dispensable for signal modulation. These findings suggest a negative immunomodulatory function for FCRL2 in the regulation of memory B cells. 相似文献