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141.
BACKGROUND: Sexual reproduction in animals requires the production of highly specialized motile sperm cells that can navigate to and fertilize ova. During sperm differentiation, nonmotile spermatids are remodeled into motile spermatozoa through a process known as spermiogenesis. In nematodes, spermiogenesis, or sperm activation, involves a rapid cellular morphogenesis that converts unpolarized round spermatids into polarized amoeboid spermatozoa capable of both motility and fertilization. RESULTS: Here we demonstrate, by genetic analysis and in vivo and in vitro cell-based assays, that the temporal and spatial localization of spermiogenesis are critical determinants of male fertility in C. elegans, a male/hermaphrodite species. We identify swm-1 as a factor important for male but not hermaphrodite fertility. We show that whereas in wild-type males, activation occurs after spermatids are transferred to the hermaphrodite, swm-1 mutants exhibit ectopic activation of sperm within the male reproductive tract. This ectopic activation leads to infertility by impeding sperm transfer. The SWM-1 protein is composed of a signal sequence and two trypsin inhibitor-like domains and likely functions as a secreted serine protease inhibitor that targets two distinct proteases. CONCLUSIONS: These findings support a model in which (1) proteolysis acts as an important in vivo trigger for sperm activation and (2) regulating the timing of proteolysis-triggered activation is crucial for male reproductive success. Furthermore, our data provide insight into how a common program of gamete differentiation can be modulated to allow males to participate in reproduction in the context of a male/hermaphrodite species where the capacity for hermaphrodite self-fertilization has rendered them nonessential for progeny production. 相似文献
142.
Michael D. L. Suits Jérôme Lang Gour P. Pal Manon Couture Zongchao Jia 《Protein science : a publication of the Protein Society》2009,18(4):825-838
For many pathogenic microorganisms, iron acquisition from host heme sources stimulates growth, multiplication, ultimately enabling successful survival and colonization. In gram‐negative Escherichia coli O157:H7, Shigella dysenteriae and Yersinia enterocolitica the genes encoded within the heme utilization operon enable the effective uptake and utilization of heme as an iron source. While the complement of proteins responsible for heme internalization has been determined in these organisms, the fate of heme once it has reached the cytoplasm has only recently begun to be resolved. Here we report the first crystal structure of ChuX, a member of the conserved heme utilization operon from pathogenic E. coli O157:H7 determined at 2.05 Å resolution. ChuX forms a dimer which remarkably given low sequence homology, displays a very similar fold to the monomer structure of ChuS and HemS, two other heme utilization proteins. Absorption spectral analysis of heme reconstituted ChuX demonstrates that ChuX binds heme in a 1:1 manner implying that each ChuX homodimer has the potential to coordinate two heme molecules in contrast to ChuS and HemS where only one heme molecule is bound. Resonance Raman spectroscopy indicates that the heme of ferric ChuX is composed of a mixture of coordination states: 5‐coordinate and high‐spin, 6‐coordinate and low‐spin, and 6‐coordinate and high‐spin. In contrast, the reduced ferrous form displays mainly a 5‐coordinate and high‐spin state with a minor contribution from a 6‐coordinate and low‐spin state. The νFe‐CO and νC‐O frequencies of ChuX‐bound CO fall on the correlation line expected for histidine‐coordinated hemoproteins indicating that the fifth axial ligand of the ferrous heme is the imidazole ring of a histidine residue. Based on sequence and structural comparisons, we designed a number of site‐directed mutations in ChuX to probe the heme binding sites and dimer interface. Spectral analysis of ChuX and mutants suggests involvement of H65 and H98 in heme coordination as mutations of both residues were required to abolish the formation of the hexacoordination state of heme‐bound ChuX. 相似文献
143.
Maika Deffieu Ingrid Bhatia-Ki??ová Bénédicte Salin Anne Galinier Stéphen Manon Nadine Camougrand 《The Journal of biological chemistry》2009,284(22):14828-14837
The antioxidant N-acetyl-l-cysteine prevented the
autophagy-dependent delivery of mitochondria to the vacuoles, as examined by
fluorescence microscopy of mitochondria-targeted green fluorescent protein,
transmission electron microscopy, and Western blot analysis of mitochondrial
proteins. The effect of N-acetyl-l-cysteine was specific
to mitochondrial autophagy (mitophagy). Indeed, autophagy-dependent activation
of alkaline phosphatase and the presence of hallmarks of non-selective
microautophagy were not altered by N-acetyl-l-cysteine.
The effect of N-acetyl-l-cysteine was not related to its
scavenging properties, but rather to its fueling effect of the glutathione
pool. As a matter of fact, the decrease of the glutathione pool induced by
chemical or genetical manipulation did stimulate mitophagy but not general
autophagy. Conversely, the addition of a cell-permeable form of glutathione
inhibited mitophagy. Inhibition of glutathione synthesis had no effect in the
strain Δuth1, which is deficient in selective mitochondrial
degradation. These data show that mitophagy can be regulated independently of
general autophagy, and that its implementation may depend on the cellular
redox status.Autophagy is a major pathway for the lysosomal/vacuolar delivery of
long-lived proteins and organelles, where they are degraded and recycled.
Autophagy plays a crucial role in differentiation and cellular response to
stress and is conserved in eukaryotic cells from yeast to mammals
(1,
2). The main form of autophagy,
macroautophagy, involves the non-selective sequestration of large portions of
the cytoplasm into double-membrane structures termed autophagosomes, and their
delivery to the vacuole/lysosome for degradation. Another process,
microautophagy, involves the direct sequestration of parts of the cytoplasm by
vacuole/lysosomes. The two processes coexist in yeast cells but their extent
may depend on different factors including metabolic state: for example, we
have observed that nitrogen-starved lactate-grown yeast cells develop
microautophagy, whereas nitrogen-starved glucose-grown cells preferentially
develop macroautophagy (3).Both macroautophagy and microautophagy are essentially non-selective, in
the way that autophagosomes and vacuole invaginations do not appear to
discriminate the sequestered material. However, selective forms of autophagy
have been observed (4) that
target namely peroxisomes (5,
6), chromatin
(7,
8), endoplasmic reticulum
(9), ribosomes
(10), and mitochondria
(3,
11–13).
Although non-selective autophagy plays an essential role in survival by
nitrogen starvation, by providing amino acids to the cell, selective autophagy
is more likely to have a function in the maintenance of cellular structures,
both under normal conditions as a “housecleaning” process, and
under stress conditions by eliminating altered organelles and macromolecular
structures
(14–16).
Selective autophagy targeting mitochondria, termed mitophagy, may be
particularly relevant to stress conditions. The mitochondrial respiratory
chain is both the main site and target of
ROS4 production
(17). Consequently, the
maintenance of a pool of healthy mitochondria is a crucial challenge for the
cells. The progressive accumulation of altered mitochondria
(18) caused by the loss of
efficiency of the maintenance process (degradation/biogenesis de
novo) is often considered as a major cause of cellular aging
(19–23).
In mammalian cells, autophagic removal of mitochondria has been shown to be
triggered following induction/blockade of apoptosis
(23), suggesting that
autophagy of mitochondria was required for cell survival following
mitochondria injury (14).
Consistent with this idea, a direct alteration of mitochondrial permeability
properties has been shown to induce mitochondrial autophagy
(13,
24,
25). Furthermore, inactivation
of catalase induced the autophagic elimination of altered mitochondria
(26). In the yeast
Saccharomyces cerevisiae, the alteration of
F0F1-ATPase biogenesis in a conditional mutant has been
shown to trigger autophagy
(27). Alterations of
mitochondrial ion homeostasis caused by the inactivation of the
K+/H+ exchanger was shown to cause both autophagy and
mitophagy (28). We have
reported that treatment of cells with rapamycin induced early ROS production
and mitochondrial lipid oxidation that could be inhibited by the hydrophobic
antioxidant resveratrol (29).
Furthermore, resveratrol treatment impaired autophagic degradation of both
cytosolic and mitochondrial proteins and delayed rapamycin-induced cell death,
suggesting that mitochondrial oxidation events may play a crucial role in the
regulation of autophagy. This existence of regulation of autophagy by ROS has
received molecular support in HeLa cells
(30): these authors showed
that starvation stimulated ROS production, namely H2O2,
which was essential for autophagy. Furthermore, they identified the cysteine
protease hsAtg4 as a direct target for oxidation by
H2O2. This provided a possible connection between the
mitochondrial status and regulation of autophagy.Investigations of mitochondrial autophagy in nitrogen-starved lactate-grown
yeast cells have established the existence of two distinct processes: the
first one occurring very early, is selective for mitochondria and is dependent
on the presence of the mitochondrial protein Uth1p; the second one occurring
later, is not selective for mitochondria, is not dependent on Uth1p, and is a
form of bulk microautophagy
(3). The absence of the
selective process in the Δuth1 mutant strongly delays and
decreases mitochondrial protein degradation
(3,
12). The putative protein
phosphatase Aup1p has been also shown to be essential in inducing mitophagy
(31). Additionally several Atg
proteins were shown to be involved in vacuolar sequestration of mitochondrial
GFP (3,
12,
32,
33). Recently, the protein
Atg11p, which had been already identified as an essential protein for
selective autophagy has also been reported as being essential for mitophagy
(33).The question remains as to identify of the signals that trigger selective
mitophagy. It is particularly intriguing that selective mitophagy is activated
very early after the shift to a nitrogen-deprived medium
(3). Furthermore, selective
mitophagy is very active on lactate-grown cells (with fully differentiated
mitochondria) but is nearly absent in glucose-grown cells
(3). In the present paper, we
investigated the relationships between the redox status of the cells and
selective mitophagy, namely by manipulating glutathione. Our results support
the view that redox imbalance is a trigger for the selective elimination of
mitochondria. 相似文献
144.
FluBlok, a recombinant trivalent hemagglutinin (rHA) vaccine produced in insect cell culture using the baculovirus expression system, provides an attractive alternative to the current egg-based trivalent inactivated influenza vaccine (TIV). Its manufacturing process presents the possibility for safe and expeditious vaccine production. FluBlok contains three times more HA than TIV and does not contain egg-protein or preservatives. The high purity of the antigen enables administration at higher doses without a significant increase in side-effects in human subjects.The insect cell–baculovirus production technology is particularly suitable for influenza where annual adjustment of the vaccine is required. The baculovirus–insect expression system is generally considered a safe production system, with limited growth potential for adventitious agents. Still regulators question and challenge the safety of this novel cell substrate as FluBlok continues to advance toward product approval. This review provides an overview of cell substrate characterization for expresSF cell line used for the manufacturing of FluBlok.In addition, this review includes an update on the clinical development of FluBlok. The highly purified protein vaccine, administered at three times higher antigen content than TIV, is well tolerated and results in stronger immunogenicity, a long lasting immune response and provides cross-protection against drift influenza viruses. 相似文献
145.
Pilar Junier Manon Frutschi Nicholas S. Wigginton Eleanor J. Schofield John R. Bargar Rizlan Bernier‐Latmani 《Environmental microbiology》2009,11(12):3007-3017
The bioremediation of uranium‐contaminated sites is designed to stimulate the activity of microorganisms able to catalyze the reduction of soluble U(VI) to the less soluble mineral UO2. U(VI) reduction does not necessarily support growth in previously studied bacteria, but it typically involves viable vegetative cells and the presence of an appropriate electron donor. We characterized U(VI) reduction by the sulfate‐reducing bacterium Desulfotomaculum reducens strain MI‐1 grown fermentatively on pyruvate and observed that spores were capable of U(VI) reduction. Hydrogen gas – a product of pyruvate fermentation – rather than pyruvate, served as the electron donor. The presence of spent growth medium was required for the process, suggesting that an unknown factor produced by the cells was necessary for reduction. Ultrafiltration of the spent medium followed by U(VI) reduction assays revealed that the factor's molecular size was below 3 kDa. Pre‐reduced spent medium displayed short‐term U(VI) reduction activity, suggesting that the missing factor may be an electron shuttle, but neither anthraquinone‐2,6‐disulfonic acid nor riboflavin rescued spore activity in fresh medium. Spores of D. reducens also reduced Fe(III)‐citrate under experimental conditions similar to those for U(VI) reduction. This is the first report of a bacterium able to reduce metals while in a sporulated state and underscores the novel nature of the mechanism of metal reduction by strain MI‐1. 相似文献
146.
Nadège Moïse Dharmendra Dingar Aida M. Mamarbachi Louis R. Villeneuve Nada Farhat Matthias Gaestel Maya Khairallah Bruce G. Allen 《Cellular signalling》2010,22(10):1502-1512
p38 MAP kinase (MAPK) isoforms α, β, and γ, are expressed in the heart. p38α appears pro-apoptotic whereas p38β is pro-hypertrophic. The mechanisms mediating these divergent effects are unknown; hence elucidating the downstream signaling of p38 should further our understanding. Downstream effectors include MAPK-activated protein kinase (MK)-3, which is expressed in many tissues including skeletal muscles and heart. We cloned full-length MK3 (MK3.1, 384 aa) and a novel splice variant (MK3.2, 266 aa) from murine heart. For MK3.2, skipping of exons 8 and 9 resulted in a frame-shift in translation of the first 85 base pairs of exon 10 followed by an in-frame stop codon. Of 3 putative phosphorylation sites for p38 MAPK, only Thr-203 remained functional in MK3.2. In addition, MK3.2 lacked nuclear localization and export signals. Quantitative real-time PCR confirmed the presence of these mRNA species in heart and skeletal muscle; however, the relative abundance of MK3.2 differed. Furthermore, whereas total MK3 mRNA was increased, the relative abundance of MK3.2 mRNA decreased in MK2?/? mice. Immunoblotting revealed 2 bands of MK3 immunoreactivity in ventricular lysates. Ectopically expressed MK3.1 localized to the nucleus whereas MK3.2 was distributed throughout the cell; however, whereas MK3.1 translocated to the cytoplasm in response to osmotic stress, MK3.2 was degraded. The p38α/β inhibitor SB203580 prevented the degradation of MK3.2. Furthermore, replacing Thr-203 with alanine prevented the loss of MK3.2 following osmotic stress, as did pretreatment with the proteosome inhibitor MG132. In vitro, GST-MK3.1 was strongly phosphorylated by p38α and p38β, but a poor substrate for p38δ and p38γ. GST-MK3.2 was poorly phosphorylated by p38α and p38β and not phosphorylated by p38δ and p38γ. Hence, differential regulation of MKs may, in part, explain diverse downstream effects mediated by p38 signaling. 相似文献
147.
The synaptonemal complex (SC) is a highly ordered proteinaceous structure that assembles at the interface between aligned homologous chromosomes during meiotic prophase. The SC has been demonstrated to function both in stabilization of homolog pairing and in promoting the formation of interhomolog crossovers (COs). How the SC provides these functions and whether it also plays a role in inhibiting CO formation has been a matter of debate. Here we provide new insight into assembly and function of the SC by investigating the consequences of reducing (but not eliminating) SYP-1, a major structural component of the SC central region, during meiosis in Caenorhabditis elegans. First, we find an increased incidence of double CO (DCO) meiotic products following partial depletion of SYP-1 by RNAi, indicating a role for SYP-1 in mechanisms that normally limit crossovers to one per homolog pair per meiosis. Second, syp-1 RNAi worms exhibit both a strong preference for COs to occur on the left half of the X chromosome and a significant bias for SYP-1 protein to be associated with the left half of the chromosome, implying that the SC functions locally in promoting COs. Distribution of SYP-1 on chromosomes in syp-1 RNAi germ cells provides strong corroboration for cooperative assembly of the SC central region and indicates that SYP-1 preferentially associates with X chromosomes when it is present in limiting quantities. Further, the observed biases in the distribution of both COs and SYP-1 protein support models in which synapsis initiates predominantly in the vicinity of pairing centers (PCs). However, discontinuities in SC structure and clear gaps between localized foci of PC-binding protein HIM-8 and X chromosome-associated SYP-1 stretches allow refinement of models for the role of PCs in promoting synapsis. Our data suggest that the CO landscape is shaped by a combination of three attributes of the SC central region: a CO-promoting activity that functions locally at CO sites, a cooperative assembly process that enables CO formation in regions distant from prominent sites of synapsis initiation, and CO-inhibitory role(s) that limit CO number.REDUCTION in ploidy during sexual reproduction depends on the ability to form pairwise associations between homologous chromosomes. The homolog pairing process typically culminates in an arrangement in which the homologs are aligned in parallel along their lengths, with a highly ordered proteinaceous structure known as the synaptonemal complex (SC) located at the interface between them. Further, in most organisms, pairwise associations between homologs are solidified through the formation of crossovers (COs) between their DNA molecules, a process that is completed within the context of the SC.The SC has long been recognized as a hallmark cytological feature of meiosis. It was discovered on the basis of its highly ordered structure and location at the interface between aligned chromosomes in electron microscopy images of nuclei at the pachytene stage of meiotic prophase (Moses 1956, 2006). Each of the homologs is associated with one of the two lateral elements (LEs) of the SC, which are composed of cohesin complexes and other meiosis-specific structural and regulatory proteins (reviewed in Mlynarczyk-Evans and Villeneuve 2010). The LEs are connected by a highly ordered latticework of transverse filaments, and often a pronounced central element, that comprise the central region of the SC. The protein components of the SC central region are very poorly conserved at the primary sequence level, but the major central region proteins identified from diverse species share in common extended regions of predicted coiled coil structure.The SC has been demonstrated to have at least two conserved functions in meiotic prophase. First, the SC serves to stabilize and maintain tight associations along the lengths of aligned homologs (reviewed in Mlynarczyk-Evans and Villeneuve 2010). This is true both in organisms in which SC assembly is coupled to formation of recombination intermediates (e.g., budding yeast, mouse, and Arabidopsis) and in organisms in which formation of SC between homologs can occur independently of recombination (e.g., Caenorhabditis elegans and Drosophila). Second, SC central region proteins play a role in promoting maturation of recombination intermediates into crossover products (reviewed in De Boer and Heyting 2006). How the SC functions to promote CO formation is not well understood. Moreover, whether the SC might also have additional functions that help to ensure a successful outcome of meiosis has been a matter of debate.In addition to its roles in stabilization of pairing and promoting CO formation, the SC has also been proposed to function in inhibiting CO formation (Egel 1978, 1995; Maguire 1988). This idea of the SC playing an inhibitory role in recombination dates almost as far back as the discovery of the SC itself. Finding a highly ordered structure with a zipper-like appearance extending along the length of each homolog pair naturally gave rise to speculation that it might play a role in the phenomenon of crossover interference, defined as the ability of a (nascent) CO to inhibit the formation of other COs nearby on the same chromosome pair (Muller 1916; Hillers 2004). It was variously proposed either that the SC might serve as a conduit of information along a chromosome pair (e.g., undergoing a distance-dependent “change in state” to inhibit COs) or that SC polymerization might itself confer CO inhibition (Egel 1978; Maguire 1988; Sym and Roeder 1994).Early analysis of the budding yeast mutants lacking Zip1, a major structural component of the SC central region, initially seemed to support the idea that the SC central region played a key role in CO interference, as zip1 mutants formed COs at 30–50% of wild-type levels and the residual COs did not display interference (Sym and Roeder 1994). However, these data were subsequently reinterpreted by postulating that the major interference-sensitive meiotic CO pathway is eliminated in the zip1 mutant and that the residual COs form by an alternative pathway that is not subject to interference (Zalevsky et al. 1999; de los Santos et al. 2003). According to this two-pathway view, the lack of interference in the zip1 mutant can be readily explained without invoking a role for Zip1 in the interference mechanism per se. Conversely, Page and Hawley found that Drosophila females expressing a mutant form of the fly SC central region protein C(3)G retained substantial interference between residual COs despite exhibiting incomplete synapsis, implying that complete SC formation was not required for CO interference (Page and Hawley 2001). In light of these and other findings (e.g., Borner et al. 2004; Fung et al. 2004), the idea that the SC might play a role in inhibiting CO formation fell from favor.In this study, we revisit a potential role for the SC central region in inhibiting CO formation, using the C. elegans experimental system. Several features make this an interesting system for investigating factors that promote and/or inhibit COs during meiosis. First, essentially all COs in C. elegans depend on conserved meiotic CO-promoting machinery (i.e., Msh4 and Msh5) and on SC central region proteins (SYP-1, -2, -3, and -4), so analysis is generally not complicated by residual COs forming by alternative pathways (Zalevsky et al. 1999; Kelly et al. 2000; MacQueen et al. 2002; Colaiacovo et al. 2003; Smolikov et al. 2007a, 2009). Second, C. elegans hermaphrodites exhibit robust CO control, with COs usually being limited to one per homolog pair per meiosis (Hillers and Villeneuve 2003; Nabeshima et al. 2004; Hammarlund et al. 2005). Consequently, circumstances that give rise to double crossover (DCO) meiotic products can be inferred to represent impairment of mechanisms that normally inhibit CO formation. Finally, COs are distributed nonuniformly along the lengths of the chromosomes, with each chromosome containing broad domains of relatively high CO frequency flanking a more central domain where CO frequency is low (Brenner 1974; Barnes et al. 1995; Rockman and Kruglyak 2009), providing an opportunity to evaluate how factors that promote and/or inhibit COs contribute to this landscape.Our strategy was to use RNAi to reduce the levels of wild-type SYP-1 protein without eliminating synapsis entirely and then to examine the effects on CO frequency and distribution. This approach indeed revealed a role for SC central region protein SYP-1 in mechanisms that normally limit the number of COs per homolog pair. Further, it also revealed a role for the SC central region in determining CO distribution, presumably by enabling formation of COs in chromosome regions distant from the dominant site of synapsis initiation. Finally, our experimental design also afforded us the opportunity to evaluate spatial distribution of the SC in the context of limiting amounts of a key central region component. This analysis provided additional insight into the process of SC assembly and the role of cis-acting meiotic pairing centers in this process. 相似文献
148.
Jerzy R. Szewczyk Chris P. Laudeman Doug M. Sammond Manon Villeneuve Douglas J. Minick Mary K. Grizzle Alejandro J. Daniels John L. Andrews Diane M. Ignar 《Bioorganic & medicinal chemistry》2010,18(5):1822-1833
Finding small non-peptide molecules for G protein-coupled receptors (GPCR) whose endogenous ligands are peptides, is a very important task for medicinal chemists. Over the years, compounds mimicking peptide structures have been discovered, and scaffolds emulating peptide backbones have been designed. In our work on GPCR ligands, including cholecystokinin receptor-1 (CCKR-1) agonists, we have employed benzodiazepines as a core structure. Looking for ways to reduce molecular weight and possibly improve physical properties of GPCR ligands, we embarked on the search for molecules providing similar scaffolds to the benzodiazepine with lower molecular weight. One of our target core structures was 1,4-dihydro-[1,4]diazepine-5,7-dione. There was not, however, a known synthetic route to such molecules. Here we report the discovery of a simple and concise method for synthesis of 2-[6-(1H-indazol-3-ylmethyl)-5,7-dioxo-4-phenyl-4,5,6,7-tetrahydro-[1,4]diazepin-1-yl]-N-isopropyl-N-phenyl-acetamide as an example of a compound containing the tetrahydrodiazepine-5,7-dione core. Compounds from this series were tested in numerous GPCR assays and demonstrated activity at melanocortin 1 and 4 receptors (MC1R and MC4R). Selected compounds from this series were tested in vivo in Peptide YY (PYY)-induced food intake. Compounds dosed by intracerebroventricular and oral routes reduced PYY-induced food intake and this effect was reversed by the cyclic peptide MC4R antagonist SHU9119. 相似文献
149.
150.
Linda Yahiaoui Annie Villeneuve Héctor Valderrama-Carvajal Fiona Burke Elizabeth D Fixman 《Cellular physiology and biochemistry》2006,17(1-2):37-46
The peptide, endothelin-1 (ET-1) regulates proliferative responses in numerous cell types. Recently, a dual ET receptor antagonist was shown to prevent the increase in airway smooth muscle cell (SMC) proliferation that accompanies airway smooth muscle remodeling in a rat model of experimental asthma. Thus, we used [(3)H]-thymidine incorporation assays and western immunoblotting to identify signaling pathways that regulate proliferative responses in cultured rat tracheal SMC. Our data indicate that ET-1 activation of the ET A receptor subtype induced [(3)H]-thymidine incorporation and activation of ERK 1/2 in primary rat tracheal SMC. ET-1-induced [(3)H]-thymidine incorporation and activation of ERK 1/2 were inhibited by pretreatment of SMC with pertussis toxin or down regulation of phorbol ester responsive isoforms of PKC. While ET- 1-induced ERK 1/2 activation was unaffected following inhibition of Rho kinase, ET-1-induced [(3)H]-thymidine incorporation was abrogated. ET-1 also potentiated [(3)H]-thymidine incorporation as well as cell proliferation of SMC stimulated with PDGF-BB and this response did not appear to be regulated by ERK1/ 2. These data demonstrate that ET-1 induces activation of multiple G proteins that regulate rat tracheal SMC proliferative responses, likely through signaling pathways downstream of ERK1/2 and Rho kinase. 相似文献