Caveolin-1 is essential for liver regeneration

Liver regeneration is an orchestrated cellular response that coordinates cell activation, lipid metabolism, and cell division. We found that caveolin-1 gene-disrupted mice (cav1-/- mice) exhibited impaired liver regeneration and low survival after a partial hepatectomy. Hepatocytes showed dramatically reduced lipid droplet accumulation and did not advance through the cell division cycle. Treatment of cav1-/- mice with glucose (which is a predominant energy substrate when compared to lipids) drastically increased survival and reestablished progression of the cell cycle. Thus, caveolin-1 plays a crucial role in the mechanisms that coordinate lipid metabolism with the proliferative response occurring in the liver after cellular injury.     

Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function

CD4+ regulatory T (Treg) cells have a profound ability to suppress host immune responses, yet little is understood about how these cells are regulated. We describe a mechanism linking Toll-like receptor (TLR) 8 signaling to the control of Treg cell function, in which synthetic and natural ligands for human TLR8 can reverse Treg cell function. This effect was independent of dendritic cells but required functional TLR8-MyD88-IRAK4 signaling in Treg cells. Adoptive transfer of TLR8 ligand-stimulated Treg cells into tumor-bearing mice enhanced anti-tumor immunity. These results suggest that TLR8 signaling could play a critical role in controlling immune responses to cancer and other diseases.     

Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis

The regenerative potential of skeletal muscle declines with age, and this impairment is associated with an increase in tissue fibrosis. We show that muscle stem cells (satellite cells) from aged mice tend to convert from a myogenic to a fibrogenic lineage as they begin to proliferate and that this conversion is mediated by factors in the systemic environment of the old animals. We also show that this lineage conversion is associated with an activation of the canonical Wnt signaling pathway in aged myogenic progenitors and can be suppressed by Wnt inhibitors. Furthermore, components of serum from aged mice that bind to the Frizzled family of proteins, which are Wnt receptors, may account for the elevated Wnt signaling in aged cells. These results indicate that the Wnt signaling pathway may play a critical role in tissue-specific stem cell aging and an increase in tissue fibrosis with age.     

Involvement of cellular caveolae in bacterial entry into mast cells

Caveolae are subcellular structures implicated in the import and transcytosis of macromolecules and in transmembrane signaling. To date, evidence for the existence of caveolae in hematopoietic cells has been ambiguous. Caveolae were detected in the microvilli and intracellular vesicles of cultured mouse bone marrow-derived mast cells (BMMCs). CD48, a receptor for FimH-expressing (type 1 fimbriated) Escherichia coli, was specifically localized to plasmalemmal caveolae in BMMCs. The involvement of caveolae in bacterial entry into BMMCs was indicated because caveolae-disrupting and -usurping agents specifically blocked E. coli entry, and markers of caveolae were actively recruited to sites of bacterial entry. The formation of bacteria-encapsulating caveolar chambers in BMMCs represents a distinct mechanism of microbial entry into phagocytes.     

Signal transduction through prion protein

The cellular prion protein PrPc is a glycosylphosphatidylinositol-anchored cell-surface protein whose biological function is unclear. We used the murine 1C11 neuronal differentiation model to search for PrPc-dependent signal transduction through antibody-mediated cross-linking. A caveolin-1-dependent coupling of PrPc to the tyrosine kinase Fyn was observed. Clathrin might also contribute to this coupling. The ability of the 1C11 cell line to trigger PrPc-dependent Fyn activation was restricted to its fully differentiated serotonergic or noradrenergic progenies. Moreover, the signaling activity of PrPc occurred mainly at neurites. Thus, PrPc may be a signal transduction protein.     

Obesity. Enzyme blocker prompts mice to shed weight

A multidisciplinary team may have discovered an important new weapon in the battle of the bulge. On page 2379 of this issue, the team reports that a molecule that is needed for fat synthesis in the body may play a key role in appetite signaling in the brain. Moreover, the investigators produced a synthetic inhibitor of this molecule that spurred a dramatic drop in appetite and weight in mice.     

Local actin polymerization and dynamin recruitment in SV40-induced internalization of caveolae

Simian virus 40 (SV40) utilizes endocytosis through caveolae for infectious entry into host cells. We found that after binding to caveolae, virus particles induced transient breakdown of actin stress fibers. Actin was then recruited to virus-loaded caveolae as actin patches that served as sites for actin "tail" formation. Dynamin II was also transiently recruited. These events depended on the presence of cholesterol and on the activation of tyrosine kinases that phosphorylated proteins in caveolae. They were necessary for formation of caveolae-derived endocytic vesicles and for infection of the cell. Thus, caveolar endocytosis is ligand-triggered and involves extensive rearrangement of the actin cytoskeleton.     

草菇VEGF信号通路中vv-SPK基因的结构与表达分析

VEGF通路是一条调控细胞增殖、分化、迁移、应激反应以及生存的信号通路。本研究从草菇基因组中获得1个在VEGF通路中编码SPK蛋白的基因,将其命名为vv-SPK,并对该基因进行结构分析,结果显示:基因vv-SPK全长1 996bp,包含11个内含子;ORF长为1 401bp,编码466个氨基酸。通过BLASTP比对显示,vv-SPK基因与纹缘盔孢伞、双色蜡蘑以及紫蜡蘑的相似度最高;经过荧光定量PCR验证后发现,SPK蛋白的基因表达量与菌柄的伸长有关。根据SPK在VEGF通路中参与的细胞增殖途径以及SPK蛋白本身的激酶特性,推测其对草菇菌柄生长过程的细胞分裂和伸长有显著的促进作用,且草菇中可能存在SPK激酶介导的促进细胞增殖、伸长的信号通路。     

A LAT mutation that inhibits T cell development yet induces lymphoproliferation

Mice homozygous for a single tyrosine mutation in LAT (linker for activation of T cells) exhibited an early block in T cell maturation but later developed a polyclonal lymphoproliferative disorder and signs of autoimmune disease. T cell antigen receptor (TCR)-induced activation of phospholipase C-gamma1 (PLC-gamma1) and of nuclear factor of activated T cells, calcium influx, interleukin-2 production, and cell death were reduced or abrogated in T cells from LAT mutant mice. In contrast, TCR-induced Erk activation was intact. These results identify a critical role for integrated PLC-gamma1 and Ras-Erk signaling through LAT in T cell development and homeostasis.     

LRP: role in vascular wall integrity and protection from atherosclerosis

Vascular smooth muscle cell (SMC) proliferation and migration are important events in the development of atherosclerosis. The low-density lipoprotein receptor-related protein (LRP1) mediates suppression of SMC migration induced by platelet-derived growth factor (PDGF). Here we show that LRP1 forms a complex with the PDGF receptor (PDGFR). Inactivation of LRP1 in vascular SMCs of mice causes PDGFR overexpression and abnormal activation of PDGFR signaling, resulting in disruption of the elastic layer, SMC proliferation, aneurysm formation, and marked susceptibility to cholesterol-induced atherosclerosis. The development of these abnormalities was reduced by treatment with Gleevec, an inhibitor of PDGF signaling. Thus, LRP1 has a pivotal role in protecting vascular wall integrity and preventing atherosclerosis by controlling PDGFR activation.     

Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases

The Rho guanosine triphosphatases (GTPases) Rac1 and Rac2 are critical signaling regulators in mammalian cells. The deletion of both Rac1 and Rac2 murine alleles leads to a massive egress of hematopoietic stem/progenitor cells (HSC/Ps) into the blood from the marrow, whereas Rac1-/- but not Rac2-/- HSC/Ps fail to engraft in the bone marrow of irradiated recipient mice. In contrast, Rac2, but not Rac1, regulates superoxide production and directed migration in neutrophils, and in each cell type, the two GTPases play distinct roles in actin organization, cell survival, and proliferation. Thus, Rac1 and Rac2 regulate unique aspects of hematopoietic development and function.     

Cell biology. Bacterial spelunkers

Bacteria that are engulfed by phagocytic cells of the immune system are usually destroyed once inside the host cell but not always. Why is it that sometimes engulfed bacteria survive and thrive quite happily inside the host cell? As Mulvey and Hultgren explain in their Perspective, the answer may lie in small indentations in the host cell plasma membrane called caveolae that direct certain signal transduction pathways inside the host cell (Shin et al.). If bacteria adhere to regions of the host cell surface that is rich in caveolae, they are better able to survive once inside the cell.     

UV-B辐照下拟南芥突变体npq4、vtc2、ndr1叶绿素荧光特性研究

通过对野生型拟南芥及npq4（非光化学猝灭减弱）、vtc2（抗坏血酸生物合成途径受阻）、ndr1（NDR1基因突变导致系统获得性抗性上游信号途径中断）3种拟南芥突变体进行UV-B周期性处理,探究其在UV-B辐照下的叶绿素荧光特性并检测其叶绿素含量。结果表明：随着UV-B辐照辐射时间的延长,野生型和突变体的NPQ、Fv/Fm、ΦPSⅡ、qN、qP、叶绿素含量及叶绿素a/b均有所降低。npq4、vtc2两个突变体的NPQ、Fv/Fm、ΦPSⅡ、叶绿素a含量及叶绿素a/b值较野生型和ndr1下降幅度大而且差异显著,表现出更严重的伤害症状。据推测,这是因为非光化学猝灭途径及抗氧化物质在植物抵抗短期高强度UV-B辐照中起重要作用,而系统获得性抗性途径不能被短期的UV-B辐照所启动,因而在植物抵抗UV-B辐照中作用较弱。     

Patched1 regulates hedgehog signaling at the primary cilium

Primary cilia are essential for transduction of the Hedgehog (Hh) signal in mammals. We investigated the role of primary cilia in regulation of Patched1 (Ptc1), the receptor for Sonic Hedgehog (Shh). Ptc1 localized to cilia and inhibited Smoothened (Smo) by preventing its accumulation within cilia. When Shh bound to Ptc1, Ptc1 left the cilia, leading to accumulation of Smo and activation of signaling. Thus, primary cilia sense Shh and transduce signals that play critical roles in development, carcinogenesis, and stem cell function.     

GT1-7细胞及其在生殖相关研究中的应用

GT1-7细胞是GT1细胞株的亚株,通过转基因技术从小鼠下丘脑分离获得的Gn RH神经元细胞系,具有高度分化的神经内分泌细胞典型特征。下丘脑Gn RH合成和释放对生殖功能具有重要作用,而Gn RH神经元在脑内数量少且呈弥散分布,体内研究较困难。目前,GT1-7细胞是研究Gn RH神经元的理想离体细胞模型,在生殖相关研究中广泛使用。文章详细阐述GT1-7细胞获得过程、功能特性及其在生殖系统研究中应用,以及影响GT1-7细胞活性的信号通路,以期对动物生殖调控研究提供参考。     

Long-term survival but impaired homeostatic proliferation of Naïve T cells in the absence of p56lck

Interactions between the T cell receptor (TCR) and major histocompatibility complex antigens are essential for the survival and homeostasis of peripheral T lymphocytes. However, little is known about the TCR signaling events that result from these interactions. The peripheral T cell pool of p56lck (lck)-deficient mice was reconstituted by the expression of an inducible lck transgene. Continued survival of peripheral na?ve T cells was observed for long periods after switching off the transgene. Adoptive transfer of T cells from these mice into T lymphopoienic hosts confirmed that T cell survival was independent of lck but revealed its essential role in TCR-driven homeostatic proliferation of na?ve T cells in response to the T cell-deficient host environment. These data suggest that survival and homeostatic expansion depend on different signals.     

Identification of Bphs,an autoimmune disease locus,as histamine receptor H1

Bphs controls Bordetella pertussis toxin (PTX)-induced vasoactive amine sensitization elicited by histamine (VAASH) and has an established role in autoimmunity. We report that congenic mapping links Bphs to the histamine H1 receptor gene (Hrh1/H1R) and that H1R differs at three amino acid residues in VAASH-susceptible and -resistant mice. Hrh1-/- mice are protected from VAASH, which can be restored by genetic complementation with a susceptible Bphs/Hrh1 allele, and experimental allergic encephalomyelitis and autoimmune orchitis due to immune deviation. Thus, natural alleles of Hrh1 control both the autoimmune T cell and vascular responses regulated by histamine after PTX sensitization.     

Checkpoint proteins control survival of the postmitotic cells in Caenorhabditis elegans

Checkpoints are evolutionarily conserved signaling mechanisms that arrest cell division and alter cellular stress resistance in response to DNA damage or stalled replication forks. To study the consequences of loss of checkpoint functions in whole animals, checkpoint genes were inactivated in the nematode C. elegans. We show that checkpoint proteins are not only essential for normal development but also determine adult somatic maintenance. Checkpoint proteins play a role in the survival of postmitotic adult cells.     

活性氧在环境胁迫诱导的植物细胞程序性死亡中的作用

细胞程序性死亡（PCD）发生在许多植物生长发育过程中和非生物的逆境条件下,是由细胞自身基因编码的、主动的、有序的细胞死亡形式。活性氧（ROS）在植物的生长、发育和对外界生物和非生物环境刺激的反应及细胞程序性死亡等调控过程中是一个重要的信号分子。本文综述了ROS的产生、对植物在环境胁迫下防御反应的作用以及与其他一些信号分子在植物PCD中的相互作用。     

Requirement for B cell linker protein (BLNK) in B cell development

Linker proteins function as molecular scaffolds to localize enzymes with substrates. In B cells, B cell linker protein (BLNK) links the B cell receptor (BCR)-activated Syk kinase to the phosphoinositide and mitogen-activated kinase pathways. To examine the in vivo role of BLNK, mice deficient in BLNK were generated. B cell development in BLNK-/- mice was blocked at the transition from B220+CD43+ progenitor B to B220+CD43- precursor B cells. Only a small percentage of immunoglobulin M++ (IgM++), but not mature IgMloIgDhi, B cells were detected in the periphery. Hence, BLNK is an essential component of BCR signaling pathways and is required to promote B cell development.