Fgf and Sdf-1 Pathways Interact during Zebrafish Fin Regeneration

The chemokine stromal cell-derived factor-1 (SDF1) was originally identified as a pre-B cell stimulatory factor but has been recently implicated in several other key steps in differentiation and morphogenesis. In addition, SDF1 as well as FGF signalling pathways have recently been shown to be involved in the control of epimorphic regeneration. In this report, we address the question of a possible interaction between the two signalling pathways during adult fin regeneration in zebrafish. Using a combination of pharmaceutical and genetic tools, we show that during epimorphic regeneration, expression of sdf1, as well as of its cognate receptors, cxcr4a, cxcr4b and cxcr7 are controlled by FGF signalling. We further show that, Sdf1a negatively regulates the expression of fgf20a. Together, these results lead us to propose that: 1) the function of Fgf in blastema formation is, at least in part, relayed by the chemokine Sdf1a, and that 2) Sdf1 exerts negative feedback on the Fgf pathway, which contributes to a transient expression of Fgf20a downstream genes at the beginning of regeneration. However this feedback control can be bypassed since the Sdf1 null mutants regenerate their fin, though slower. Very few mutants for the regeneration process were isolated so far, illustrating the difficulty in identifying genes that are indispensable for regeneration. This observation supports the idea that the regeneration process involves a delicate balance between multiple pathways.     

LKB1 Controls Human Bronchial Epithelial Morphogenesis through p114RhoGEF-Dependent RhoA Activation

LKB1 is a Ser/Thr kinase that plays an important role in controlling both energy metabolism and cell polarity in metazoan organisms. LKB1 is also a tumor suppressor, and homozygous, inactivating mutations are found in a wide range of human cancers. In lung cancer, inactivating mutations are found in 10 to 50% of cases, but the consequences of functional loss in this context are poorly understood. We report here that LKB1 is required for the maturation of apical junctions in the human bronchial epithelial cell line 16HBE14o- (16HBE). This activity is dependent on an interaction with the Rho guanine nucleotide exchange factor p114RhoGEF but is independent of LKB1 kinase activity. Together, LKB1 and p114RhoGEF control RhoA activity in these cells to promote apical junction assembly.     

LKB1 Mediates the Development of Conventional and Innate T Cells via AMP-Dependent Kinase Autonomous Pathways

The present study has examined the role of the serine/threonine kinase LKB1 in the survival and differentiation of CD4/8 double positive thymocytes. LKB1-null DPs can respond to signals from the mature α/β T-cell-antigen receptor and initiate positive selection. However, in the absence of LKB1, thymocytes fail to mature to conventional single positive cells causing severe lymphopenia in the peripheral lymphoid tissues. LKB1 thus appears to be dispensable for positive selection but important for the maturation of positively selected thymocytes. LKB1 also strikingly prevented the development of invariant Vα14 NKT cells and innate TCR αβ gut lymphocytes. Previous studies with gain of function mutants have suggested that the role of LKB1 in T cell development is mediated by its substrate the AMP-activated protein kinase (AMPK). The present study now analyses the impact of AMPK deletion in DP thymocytes and shows that the role of LKB1 during the development of both conventional and innate T cells is mediated by AMPK-independent pathways.     

The Arginine Decarboxylase Pathways of Host and Pathogen Interact to Impact Inflammatory Pathways in the Lung

The arginine decarboxylase pathway, which converts arginine to agmatine, is present in both humans and most bacterial pathogens. In humans agmatine is a neurotransmitter with affinities towards α2-adrenoreceptors, serotonin receptors, and may inhibit nitric oxide synthase. In bacteria agmatine serves as a precursor to polyamine synthesis and was recently shown to enhance biofilm development in some strains of the respiratory pathogen Pseudomonas aeruginosa. We determined agmatine is at the center of a competing metabolism in the human lung during airways infections and is influenced by the metabolic phenotypes of the infecting pathogens. Ultra performance liquid chromatography with mass spectrometry detection was used to measure agmatine in human sputum samples from patients with cystic fibrosis, spent supernatant from clinical sputum isolates, and from bronchoalvelolar lavage fluid from mice infected with P. aeruginosa agmatine mutants. Agmatine in human sputum peaks during illness, decreased with treatment and is positively correlated with inflammatory cytokines. Analysis of the agmatine metabolic phenotype in clinical sputum isolates revealed most deplete agmatine when grown in its presence; however a minority appeared to generate large amounts of agmatine presumably driving sputum agmatine to high levels. Agmatine exposure to inflammatory cells and in mice demonstrated its role as a direct immune activator with effects on TNF-α production, likely through NF-κB activation. P. aeruginosa mutants for agmatine detection and metabolism were constructed and show the real-time evolution of host-derived agmatine in the airways during acute lung infection. These experiments also demonstrated pathogen agmatine production can upregulate the inflammatory response. As some clinical isolates have adapted to hypersecrete agmatine, these combined data would suggest agmatine is a novel target for immune modulation in the host-pathogen dynamic.     

LKB1及其生物学功能

LKB1基因是一种保守的抑癌基因,其编码产物LKB1即丝氨酸-苏氨酸激酶11(serine/threonine kinase,STK11)。LKB1与细胞极性调节、男性精子形成、肿瘤及细胞代谢等方面有关。本文阐述了近年来LKB1的最新研究进展。     

LKB1-AMPK axis revisited

The LKB1 tumor suppressor encodes a serine-threonine kinase whose substrates control cell metabolism, polarity, and motility. LKB1 is a major mediator of the cellular response to energy stress via activation of the master regulator of energy homeostasis, AMPK. While mutational inactivation of LKB1 promotes the development of many types of epithelial cancer, a recent report in Nature by Jeon et al. demonstrates that the LKB1-AMPK pathway can also have an unexpected positive role in tumorigenesis, acting to maintain metabolic homeostasis and attenuate oxidative stress thereby supporting the survival of cancer cells.Normal mammalian cells possess adaptive mechanisms that enable coupling of nutrient availability with demand via integrated control of growth and metabolism. The widespread deregulation of these processes is now recognized as a prominent hallmark of all cancers. A key nutrient sensor in normal and cancer cells is the LKB1-AMPK axis, which is critical for maintenance of metabolic homeostasis¹. In response to energy stress (and resulting increase in AMP:ATP ratio), LKB1 phosphorylates AMPK, which in turn phosphorylates numerous substrates controlling diverse metabolic processes, with the net effect of shifting the balance from anabolic to catabolic function and thereby restoring cellular ATP levels. LKB1 is an established tumor suppressor that is mutationally inactivated in a wide variety of epithelial cancers and promotes tumorigenesis when deleted in mouse models. While the underlying mechanisms for LKB1-mediated tumor suppression are not fully defined, the key role of AMPK in inactivating mTOR is thought to contribute to this process^1,2.An interesting paradox given this function as a tumor suppressor emerges from the observations that LKB1 or AMPK deletion renders primary cells resistant to transformation by overexpressed oncogenes and causes decreased viability of both cancer cell lines and primary cells under energy stress conditions^3,4,5,6,7,8. The significance of the survival function of the LKB1-AMPK axis in cancer pathogenesis and the associated molecular mechanisms are the main focus of a recent report by Jeon et al.⁹.In this study, the authors utilized the A549 lung cancer cell line, which exhibits homozygous inactivating mutations of endogenous LKB1, as a model to study LKB1-AMPK-dependent survival under energy stress. Reintroduction of LKB1 resulted in the expected activation of AMPK and improved cell survival upon glucose deprivation. This effect was independent of mTOR or p53 inactivation, insofar as rapamycin treatment or p53 dominant-negative coexpression did not affect the starvation-induced cell death in A549 vector-transduced (i.e., control) cells.Glucose starvation inhibits the pentose phosphate pathway (PPP), which is an important mechanism for NADPH production and consequent H₂O₂ detoxification (Figure 1). To survive in this setting, cells require compensatory NADPH generation, produced by other biochemical pathways. The authors hypothesized that a requirement for LKB1 in this adaptive NAPDH production may underlie its survival function in glucose-deprived cells. Consistent with this hypothesis, they showed that treatment with N-acetylcysteine or catalase, both antioxidants, inhibited starvation-induced death of both LKB1- and AMPK-deficient (A549/HeLa and MEFs, respectively) cells. In addition, metabolic analysis of the glucose-starved A549 cells revealed that the ratios of NADP/NADPH and oxidized glutathione/reduced glutathione (GSSG/GSH) were maintained in LKB1-transduced cells, whereas both ratios were increased in the vector-transduced cells. Since NAPDH is mainly utilized to reduce GSSG to its GSH form, which is in turn used to detoxify cells from H₂O₂ through the function of glutathione peroxidase, these results reveal that the LKB1-AMPK axis has a central role in suppressing oxidative stress (Figure 1).Open in a separate windowFigure 1AMPK is phosphorylated and activated by LKB1 in response to an increasing cellular AMP:ATP ratio (which reflects a decrease in energy supply). AMPK in turn phosphorylates and inactivates ACC1/2, promoting a shift from fatty acid synthesis (FAS) to fatty acid oxidation (FAO). FAS depletes NADPH that is required for H₂O₂ detoxification. FAO, by contrast, produces metabolites that are used by the TCA cycle, resulting in increased NADPH and enhanced cell survival. This pathway may only be transiently activated in glucose-deprived cells since ATP, produced by the coupling the TCA cycle with oxidative phosphorylation (OXPHOS), will eventually inhibit AMPK. In addition to the role of the LKB1-AMPK pathway in facilitating tumor cell survival, LKB1 is a context-specific tumor suppressor, which acts to control cell polarity and restrict cell growth via mTOR inactivation and induction of other AMPK-related kinases.Upon glucose starvation and consequent loss of PPP function, the major contributor to NADPH generation is mitochondrial metabolism whose activity is maintained by fatty acid oxidation in this context. The rate-limiting enzyme in catabolism of fatty acids is carnitine palmitoyltransferase 1 (CPT1). Under normal conditions, CPT1 is inhibited by the malonyl-CoA produced by acetyl-CoA carboxylase alpha (ACC1) and acetyl-CoA carboxylase beta (ACC2). These two enzymes are subject to inhibition by phosphorylation by AMPK¹⁰. Therefore, the authors hypothesized that LKB1-AMPK may control the levels of NADPH by inhibiting ACC1 and ACC2. Targeted knockdown studies revealed that ACC2 inactivation was sufficient to restore NADP/NADPH and GSSG/GSH ratios and to rescue cell death in glucose-starved A549 cells. These findings were extended by a set of experiments using the constitutively active ACC2 (S212A) mutant, the fatty acid synthase (FAS) inhibitor C75, the ACC inhibitor TOFA, malate supplement, buthionine sulphoximine (which depletes GSH), and nicotinamide, that together support the hypothesis that survival under glucose starvation is dependent on the inactivation of ACC2 (and ACC1 in some cell types) by AMPK-regulated phosphorylation.Matrix detachment impairs cell viability in part due to induction of energy stress, leading to NADPH depletion and increased H₂O₂ levels. The authors found that the LKB1-AMPK axis also plays a pro-survival role in this setting. LKB1-null cells have reduced viability and impaired growth under anchorage-independent conditions, due mainly to decreased NADPH levels and subsequent oxidative stress.Cancer cells need to activate survival mechanisms to cope with energy stress and matrix detachment during tumor progression. Thus, the authors speculated that the LKB1-AMPK-ACC1/2-NADPH pathway might play an important role in promoting tumor growth. Correspondingly, NAC treatment or shRNA-mediated knockdown of ACC1/2 increased anchorage-independent growth of A549 cells in soft agar, and ACC1/2 knockdown enhanced tumorigenicity in xenograft studies. Moreover, similar effects were seen using RAS V12-transformed AMPKα^−/− MEF cells with concurrent ACC1/2 knockdown, consistent with LKB1 and AMPK acting in a common pathway to promote tumorigenesis.The results described above were obtained mainly in the setting of ectopically restoring LKB1 in LKB1-deficient cancer cells. An important question that is raised by these findings is whether cancers that arise with an intact LKB1-AMPK axis require this pathway for sustained tumorigenesis. To address this issue, the authors examined the impact of knockdown of either LKB1 or AMPKα1 in MCF7 breast cancer cells. These manipulations reduced xenograft tumor formation, as did overexpression of the constitutively active, phosphorylation-deficient mutants ACC mutant (ACC1-S79A or ACC2-S212A). Collectively, these observations indicate that activation of AMPK and consequent inactivation of ACC1/2 by endogenous AMPK is an important survival mechanism in cancer (Figure 1).These conclusions are of particular note considering the established role of LKB1 in tumor suppression. This tumor suppressive function may involve the ability of the LKB1-AMPK pathway to promote mTOR inactivation by TSC2 and raptor phosphorylation^1,2, as well as functions of other members of the family of AMPK-related kinases. Since mTOR activation is a common feature of cancer and a driver of many tumor types, it may seem counterintuitive to assign a tumorigenic role in one of its major inhibitors. Another layer of complexity stems from the fact that AMPK activation is unlikely to be sustained for prolonged period of time. Fatty acid oxidation, activated by AMPK during glucose starvation, will feed into the TCA-oxidative phosphorylation cycles, in turn leading to ATP production and AMP:ATP ratio decrease, followed by AMPK inactivation (Figure 1). To reconcile these two opposing functions of AMPK, the authors suggest that this negative feedback loop is a reflection of the temporal manner of AMPK activation that, at physiological levels, is essential for the survival of the tumor cells during energy stress (starvation or matrix detachment) but it is quickly followed by inactivation. According to this model, use of LKB1 or AMPK inhibitors in acute regimens could prove beneficial for cancer therapy by sensitizing cells to energy stress. Moreover, the acute nature of the treatment could potentially cause metabolic stress, sensitizing cells to other chemotherapy regiments. Sustained inactivation of the LKB1-AMPK pathway on the other hand, could result in long-term stress, promote rewiring of intracellular metabolic processes, and tip the balance towards increased proliferation due to activation of mTOR and other pathways.Based on these results, a major question is raised: How do LKB1-deficient tumors bypass the normal requirement for the LKB1-AMPK axis in energy stress response? Presumably, LKB1 inactivation must occur in the context of specific cooperating molecular alterations that enable cell survival despite these impairments in metabolic homeostasis, thereby allowing the pro-tumorigenic consequences of LKB1 loss to take hold. One potential escape route could involve alternative, LKB1-independent mechanisms for AMPK activation such as induction of CAMK2 or a hexokinase-dependent pathway¹, but other pathways could be equally important. Further studies will likely uncover additional adaptive processes permitting cell survival under metabolic stress in the absence of LKB1. Metabolic profiling of LKB1 null tumors could provide a glimpse of these alternative pathways, opening the way for new targeted therapeutic strategies. Moreover, cancer genome sequencing efforts are likely to reveal specific complementation groups of mutations that coexist with LKB1 mutations in different cancer types or are mutually exclusive, reflecting molecular pathways that synergize with LKB1 deficiency. Additionally, other important AMPK-independent functions of LKB1 should also be brought into focus. In this regard, AMPKα1/2 are constituents of a 14-member family of kinases that are phosphorylated and activated by LKB1 and that broadly include regulators of epithelial cell polarity as well as metabolism. Disruption of polarity, as altered metabolism, is a hallmark of epithelial cancer progression¹¹, and the relative roles of these processes downstream of LKB1 in growth control is an area of active investigation. Indeed, inactivation of LKB1 produces dramatic invasive and migratory phenotypes in different cancer models^12,13,14. The findings of Jeon et al.⁹ may thus presage that the LKB1-AMPK axis is only a minor component of the LKB1 tumor suppressor program compared to its functions in metabolic adaptation and cell survival.Long-term use of metformin, in the treatment of Type II diabetes, has been shown to reduce tumor incidence and sensitizes multiple cancer cell types to chemotherapy¹. Furthermore, LKB1 controls hepatic glucose metabolism and the therapeutic effects of metformin. A recent study that revealed that AMPK is activated by salicylate also suggests that this mechanism is, at least partly, responsible for the cancer-protective effects of aspirin¹⁵. On the other hand, inhibition of LKB1-AMPK sensitizes cancer cells to energy stress-induced apoptosis. Therefore, the results presented by Jeon et al.⁹ suggest that targeting the LKB1-AMPK axis in cancer should be done with caution and with attention to specific contexts.     

Inflammation and MiR-21 Pathways Functionally Interact to Downregulate PDCD4 in Colorectal Cancer

Inflammation plays a direct role in colorectal cancer (CRC) progression; however the molecular mechanisms responsible for this effect are unclear. The inflammation induced cyclooxygenase 2 (COX-2) enzyme required for the production of Prostaglandin E2 (PGE₂), can promote colorectal cancer by decreasing expression of the tumour suppressor gene Programmed Cell Death 4 (PDCD4). As PDCD4 is also a direct target of the oncogene microRNA-21 (miR-21) we investigated the relationship between the COX-2 and miR-21 pathways in colorectal cancer progression. Gene expression profile in tumour and paired normal mucosa from 45 CRC patients demonstrated that up-regulation of COX-2 and miR-21 in tumour tissue correlates with worse Dukes'' stage. In vitro studies in colonic adenocarcinoma cells revealed that treatment with the selective COX-2 inhibitor NS398 significantly decreased miR-21 levels (p = 0.0067) and increased PDCD4 protein levels (p<0.001), whilst treatment with PGE₂ up-regulated miR-21 expression (p = 0.019) and down-regulated PDCD4 protein (p<0.05). These findings indicate that miR-21 is a component of the COX-2 inflammation pathway and that this pathway promotes worsening of disease stage in colorectal cancer by inducing accumulation of PGE₂ and increasing expression of miR-21 with consequent downregulation of the tumour suppressor gene PDCD4.     

Protein kinase Czeta-dependent LKB1 serine 428 phosphorylation increases LKB1 nucleus export and apoptosis in endothelial cells

LKB1 is a serine-threonine protein kinase that, when inhibited, may result in unregulated cell growth and tumor formation. However, how LKB1 is regulated remains poorly understood. The aim of the present study was to define the upstream signaling events responsible for peroxynitrite (ONOO(-))-induced LKB1 activation. Exposure of cultured human umbilical vein endothelial cells to a low concentration of ONOO(-) (5 microM) significantly increased the phosphorylation of LKB1 at Ser(428) and protein kinase Czeta (PKCzeta) at Thr(410). These effects were accompanied by increased activity of the lipid phosphatase PTEN, decreased activity and phosphorylation (Ser(473)) of Akt, and induction of apoptosis. ONOO(-) enhanced Akt-Ser(473) phosphorylation in LKB1-deficient HeLa S3 cells or in HeLa S3 cells transfected with kinase-dead LKB1. Conversely, ONOO(-) inhibited Akt Ser(473) phosphorylation when wild type LKB1 were reintroduced in HeLa S3 cells. Further analysis revealed that PKCzeta directly phosphorylated LKB1 at Ser(428) in vitro and in intact cells, resulting in increased PTEN phosphorylation at Ser(380)/Thr(382/383). Finally, ONOO(-) enhanced PKCzeta nuclear import and LKB1 nuclear export. We conclude that PKCzeta mediates LKB1-dependent Akt inhibition in response to ONOO(-), resulting in endothelial apoptosis.     

Targeting LKB1 signaling in cancer

The serine/threonine kinase LKB1 is a master kinase involved in cellular responses such as energy metabolism, cell polarity and cell growth. LKB1 regulates these crucial cellular responses mainly via AMPK/mTOR signaling. Germ-line mutations in LKB1 are associated with the predisposition of the Peutz–Jeghers syndrome in which patients develop gastrointestinal hamartomas and have an enormously increased risk for developing gastrointestinal, breast and gynecological cancers. In addition, somatic inactivation of LKB1 has been associated with sporadic cancers such as lung cancer. The exact mechanisms of LKB1-mediated tumor suppression remain so far unidentified; however, the inability to activate AMPK and the resulting mTOR hyperactivation has been detected in PJS-associated lesions. Therefore, targeting LKB1 in cancer is now mainly focusing on the activation of AMPK and inactivation of mTOR. Preclinical in vitro and in vivo studies show encouraging results regarding these approaches, which have even progressed to the initiation of a few clinical trials. In this review, we describe the functions, regulation and downstream signaling of LKB1, and its role in hereditary and sporadic cancers. In addition, we provide an overview of several AMPK activators, mTOR inhibitors and additional mechanisms to target LKB1 signaling, and describe the effect of these compounds on cancer cells. Overall, we will explain the current strategies attempting to find a way of treating LKB1-associated cancer.     

LKB1抑癌机制研究进展

人LKB1(Liver Kinase B1,或Serine-Threonine Kinase 11,STK11)基因的胚系失活突变可导致癌症易感病皮杰氏综合征(Peutz-Jeghers syndrome,PJS),该病患者多发错构瘤息肉且患癌症风险增加。LKB1基因的体细胞突变还广泛地存在于众多类型的恶性肿瘤中,如肺癌、结肠癌和乳腺癌等,因此,LKB1被普遍认为是抑癌基因。LKB1基因的编码产物LKB1是一种丝氨酸/苏氨酸激酶,调节多种细胞生理病理过程。虽然LKB1的抑癌机制尚不完全清楚,但现有的研究表明,对细胞生长增殖、能量代谢和细胞极性等的调控是其抑制肿瘤发生和发展的重要方面。本文就目前已知的LKB1的抑癌机制作一综述。     

BMP and Notch Signaling Pathways differentially regulate Cardiomyocyte Proliferation during Ventricle Regeneration

Adult mammalian hearts show limited capacity to proliferate after injury, while zebrafish are capable to completely regenerate injured hearts through the proliferation of spared cardiomyocytes. BMP and Notch signaling pathways have been implicated in cardiomyocyte proliferation during zebrafish heart regeneration. However, the molecular mechanism underneath this process as well as the interaction between these two pathways remains to be further explored. In this study we showed BMP signaling was activated after ventricle ablation and acted epistatic downstream of Notch signaling. Inhibition of both signaling pathways differentially influenced ventricle regeneration and cardiomyocyte proliferation, as revealed by time-lapse analysis using a cardiomyocyte-specific FUCCI (fluorescent ubiquitylation-based cell cycle indicator) system. Further experiments revealed that inhibition of BMP and Notch signaling led to cell-cycle arrest at different phases. Overall, our results shed light on the interaction between BMP and Notch signaling pathways and their functions in cardiomyocyte proliferation during cardiac regeneration.     

Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2

Proteins encoded by the fringe family of genes are required to modulate Notch signalling in a wide range of developmental contexts. Using a cell co-culture assay, we find that mammalian Lunatic fringe (Lfng) inhibits Jagged1-mediated signalling and potentiates Delta1-mediated signalling through Notch1. Lfng localizes to the Golgi, and Lfng-dependent modulation of Notch signalling requires both expression of Lfng in the Notch-responsive cell and the Notch extracellular domain. Lfng does not prevent binding of soluble Jagged1 or Delta1 to Notch1-expressing cells. Lfng potentiates both Jagged1- and Delta1-mediated signalling via Notch2, in contrast to its actions with Notch1. Our data suggest that Fringe-dependent differential modulation of the interaction of Delta/Serrate/Lag2 (DSL) ligands with their Notch receptors is likely to have a significant role in the combinatorial repertoire of Notch signalling in mammals.     

Lovastatin Induces Multiple Stress Pathways Including LKB1/AMPK Activation That Regulate Its Cytotoxic Effects in Squamous Cell Carcinoma Cells

Background

Cellular stress responses trigger signaling cascades that inhibit proliferation and protein translation to help alleviate the stress or if the stress cannot be overcome induce apoptosis. In recent studies, we demonstrated the ability of lovastatin, an inhibitor of mevalonate synthesis, to induce the Integrated Stress Response as well as inhibiting epidermal growth factor receptor (EGFR) activation.

Methodology/Principal Findings

In this study, we evaluated the effects of lovastatin on the activity of the LKB1/AMPK pathway that is activated upon cellular energy shortage and can interact with the above pathways. In the squamous cell carcinoma (SCC) cell lines SCC9 and SCC25, lovastatin treatment (1–25 µM, 24 hrs) induced LKB1 and AMPK activation similar to metformin (1–10 mM, 24 hrs), a known inducer of this pathway. Lovastatin treatment impaired mitochondrial function and also decreased cellular ADP/ATP ratios, common triggers of LKB1/AMPK activation. The cytotoxic effects of lovastatin were attenuated in LKB1 null MEFs indicating a role for this pathway in regulating lovastatin-induced cytotoxicity. Of clinical relevance, lovastatin induces synergistic cytotoxicity in combination with the EGFR inhibitor gefitinib. In LKB1 deficient (A549, HeLa) and expressing (SCC9, SCC25) cell lines, metformin enhanced gefitinib cytotoxicity only in LKB1 expressing cell lines while both groups showed synergistic cytotoxic effects with lovastatin treatments. Furthermore, the combination of lovastatin with gefitinib induced a potent apoptotic response without significant induction of autophagy that is often induced during metabolic stress inhibiting cell death.

Conclusion/Significance

Thus, targeting multiple metabolic stress pathways including the LKB1/AMPK pathway enhances lovastatin’s ability to synergize with gefitinib in SCC cells.     

胚珠发育的分子机理

胚珠是研究器官形态发生和模式建成遗传分子机理的一个理想系统。近年来, 关于胚珠特征的决定、模式建成、珠被形态建成和胚囊形成等发育事件分子机理的研究取得了重要进展, 初步建立了胚珠发育的基因调控模型。同时, 离体花器官再生系统为研究激素调控胚珠发育的机理提供了有效途径。本文对拟南芥(Arabidopsis thaliana)胚珠发育的分子调控机制进行了综述。     

胚珠发育的分子机理

胚珠是研究器官形态发生和模式建成遗传分子机理的一个理想系统.近年来,关于胚珠特征的决定、模式建成、珠被形态建成和胚囊形成等发育事件分子机理的研究取得了重要进展,初步建立了胚珠发育的基因调控模型.同时,离体花器官再生系统为研究激素调控胚珠发育的机理提供了有效途径.本文对拟南芥(Arabidopsis thaliana)胚珠发育的分子调控机制进行了综述.     

LKB1 and AMPK in cell polarity and division

LKB1 and AMP-activated protein kinase (AMPK) are serine-threonine kinases implicated in key cellular pathways, including polarity establishment and energy sensing, respectively. Recent in vivo analyses in Drosophila have demonstrated vital roles for both AMPK and LKB1--in part through the myosin regulatory light chain--in cell polarity and cell division. Evidence from mammalian experiments also supports non-metabolic functions for LKB1 and AMPK. This review examines unanticipated AMPK functions for initiating and maintaining cell polarity and completing normal cell division. The ability of AMPK to sense energy status might be coupled with fundamental cell biological functions.