HSP90 regulates cell survival via inositol hexakisphosphate kinase-2

Heat-shock proteins (HSPs) are abundant, inducible proteins best known for their ability to maintain the conformation of proteins and to refold damaged proteins. Some HSPs, especially HSP90, can be antiapoptotic and the targets of anticancer drugs. Inositol hexakisphosphate kinase-2 (IP6K2), one of a family of enzymes generating the inositol pyrophosphate IP7 [diphosphoinositol pentakisphosphate (5-PP-IP5)], mediates apoptosis. Increased IP6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death. We now show that HSP90 physiologically binds IP6K2 and inhibits its catalytic activity. Drugs and selective mutations that abolish HSP90-IP6K2 binding elicit activation of IP6K2, leading to cell death. Thus, the prosurvival actions of HSP90 reflect the inhibition of IP6K2, suggesting that selectively blocking this interaction could provide effective and safer modes of chemotherapy.     

Meis1 regulates proliferation of non-small-cell lung cancer cells

As one of the most common cancers, lung cancer remains to be a major public health problem. Non-small-cell lung adenocarcinoma cancer exhibits higher resistance to chemotherapy than small cell lung cancer, which requires novel strategies. To further understand underlying mechanisms for non-small-cell lung adenocarcinoma cancer cell proliferation, we explored the role of Meis1 in non-small-cell lung adenocarcinoma cancer cells. The results show that Meis1 inhibits non-small-cell lung cancer (NSCLC) cell proliferation. Specific knockdown of Meis1 resulted in strengthened proliferative ability of non-small-cell lung adenocarcinoma cancer cells. Cell cycle analysis indicated that DNA synthesis was increased when Meis1 was down-regulated specifically. As well as histone H3 phosphorylation, which is indicative of mitosis. More importantly, forced Meis1 expression repressed the proliferation of non-small-cell lung adenocarcinoma cancer cell. These data demonstrated Meis1 limits the proliferation of non-small-cell lung adenocarcinoma cancer cell and could potentially represent a therapeutic strategy that may control non-small-cell lung adenocarcinoma cancer cell proliferation.     

Preventing hypoxia-induced cell death in beta cells and islets via hydrolytically activated, oxygen-generating biomaterials

A major hindrance in engineering tissues containing highly metabolically active cells is the insufficient oxygenation of these implants, which results in dying or dysfunctional cells in portions of the graft. The development of methods to increase oxygen availability within tissue-engineered implants, particularly during the early engraftment period, would serve to allay hypoxia-induced cell death. Herein, we designed and developed a hydrolytically activated oxygen-generating biomaterial in the form of polydimethylsiloxane (PDMS)-encapsulated solid calcium peroxide, PDMS-CaO(2). Encapsulation of solid peroxide within hydrophobic PDMS resulted in sustained oxygen generation, whereby a single disk generated oxygen for more than 6 wk at an average rate of 0.026 mM per day. The ability of this oxygen-generating material to support cell survival was evaluated using a β cell line and pancreatic rat islets. The presence of a single PDMS-CaO(2) disk eliminated hypoxia-induced cell dysfunction and death for both cell types, resulting in metabolic function and glucose-dependent insulin secretion comparable to that in normoxic controls. A single PDMS-CaO(2) disk also sustained enhanced β cell proliferation for more than 3 wk under hypoxic culture conditions. Incorporation of these materials within 3D constructs illustrated the benefits of these materials to prevent the development of detrimental oxygen gradients within large implants. Mathematical simulations permitted accurate prediction of oxygen gradients within 3D constructs and highlighted conditions under which supplementation of oxygen tension would serve to benefit cellular viability. Given the generality of this platform, the translation of these materials to other cell-based implants, as well as ischemic tissues in general, is envisioned.     

TAK1 regulates hepatic cell survival and carcinogenesis

TGF-β-activated kinase 1 (TAK1 or MAP3K7) is an intracellular hub molecule that regulates both nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways that play key roles in development, cell survival, immune response, metabolism, and carcinogenesis. TAK1 activity is tightly regulated by its binding proteins, TAB1 and TAB2/TAB3, as well as by post-translational modification including ubiquitination and phosphorylation. Accumulating evidence demonstrates that TAK1 plays a role in tumor initiation, progression, and metastasis as a tumor prompter or tumor suppressor. An understanding of the role of TAK1 in liver physiology and diseases is required for the development of therapeutic agencies targeting TAK1. In this review, we highlight the activation mechanism and pathophysiological roles of TAK1 in the liver.     

Endocannabinoid regulation of β‐cell functions: implications for glycaemic control and diabetes

Visceral obesity is a major risk factor for the development of insulin resistance which can progress to overt type 2 diabetes (T2D) with loss of β‐cell function and, ultimately, loss of β‐cells. Insulin secretion by β‐cells of the pancreatic islets is tightly coupled to blood glucose concentration and modulated by a large number of blood‐borne or locally released mediators, including endocannabinoids. Obesity and its complications, including T2D, are associated with increased activity of the endocannabinoid/CB₁ receptor (CB₁R) system, as indicated by the therapeutic effects of CB₁R antagonists. Similar beneficial effects of CB₁R antagonists with limited brain penetrance indicate the important role of CB₁R in peripheral tissues, including the endocrine pancreas. Pancreatic β‐cells express all of the components of the endocannabinoid system, and endocannabinoids modulate their function via both autocrine and paracrine mechanisms, which influence basal and glucose‐induced insulin secretion and also affect β‐cell proliferation and survival. The present brief review will survey available information on the modulation of these processes by endocannabinoids and their receptors, with an attempt to assess the contribution of such effects to glycaemic control in T2D and insulin resistance.     

支链氨基酸氨基转移酶1通过P53信号调节脂肪间充质干细胞存活

目的 研究支链氨基酸氨基转移酶1(branched-chain-amino-acid aminotransferase 1,BCAT1)调节间充质干细胞存活的作用并探讨机制。 方法 从雄性Sprague Dawley大鼠附睾白色脂肪中分离脂肪间充质干细胞（adipose-derived mesenchymal stem cells,ADSCs）。腺病毒转染ADSCs中分别过表达或敲低BCAT1表达后给予过氧化氢（hydrogen dioxide,H₂O₂）刺激诱导ADSCs凋亡。利用CCK-8细胞活力分析、cleaved caspase-3表达及TUNEL染色评估ADSCs凋亡。利用P53特异性抑制剂PFT-1α探讨P53信号在BCAT1调节ADSCs生存的分子机制。 结果 BCAT1而不是BCAT2是ADSCs的主要表达亚型。H₂O₂刺激诱导ADSCs凋亡时BCAT1蛋白表达水平显著降低（P<0.01）。使用shRNA敲低BCAT1表达加重而过表达BCAT1显著减轻H₂O₂诱导的ADSCs凋亡（均P<0.01）。敲低BCAT1导致H₂O₂刺激的ADSCs中P53下游靶基因表达水平显著增高,提示P53信号活化（均P<0.01）。PFT-1α可以逆转BCAT1敲低恶化的ADSCs凋亡（均P<0.01）。 结论 BCAT1通过P53信号调节ADSCs生存。BCAT1可作为促进ADSCs存活、增强其心肌保护作用的候选靶点。     

DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis

In metastatic prostate cancer (PCa) cells, imbalance between cell survival and death signals such as constitutive activation of phosphatidylinositol 3-kinase (PI3K)-Akt and inactivation of apoptosis-stimulated kinase (ASK1)-JNK pathways is often detected. Here, we show that DAB2IP protein, often down-regulated in PCa, is a potent growth inhibitor by inducing G₀/G₁ cell cycle arrest and is proapoptotic in response to stress. Gain of function study showed that DAB2IP can suppress the PI3K-Akt pathway and enhance ASK1 activation leading to cell apoptosis, whereas loss of DAB2IP expression resulted in PI3K-Akt activation and ASK1-JNK inactivation leading to accelerated PCa growth in vivo. Moreover, glandular epithelia from DAB2IP^−/− animal exhibited hyperplasia and apoptotic defect. Structural functional analyses of DAB2IP protein indicate that both proline-rich (PR) and PERIOD-like (PER) domains, in addition to the critical role of C2 domain in ASK1 activity, are important for modulating PI3K-Akt activity. Thus, DAB2IP is a scaffold protein capable of bridging both survival and death signal molecules, which implies its role in maintaining cell homeostasis.     

Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3'-Kinase/Akt signal transduction pathway

Angiopoietin-1 (Ang1) is a strong apoptosis survival factor for endothelial cells. In this study, the receptor/second messenger signal transduction pathway for the antiapoptotic effect of Ang1 on human umbilical vein endothelial cells was examined. Pretreatment with soluble Tie2 receptor, but not Tie1 receptor, blocked the Ang1-induced antiapoptotic effect. Ang1 induced phosphorylation of Tie2 and the p85 subunit of phosphatidylinositol 3'-kinase (PI 3'-kinase) and increased PI 3'-kinase activity in a dose-dependent manner. The PI 3'-kinase-specific inhibitors wortmannin and LY294002 blocked the Ang1-induced antiapoptotic effect. Ang1 induced phosphorylation of the serine-threonine kinase Akt at Ser473 in a PI 3'-kinase-dependent manner. Expression of a dominant-negative form of Akt reversed the Ang1-induced antiapoptotic effect. Ang1 mRNA and protein were present in vascular smooth muscle cells but not in endothelial cells. Cultured vascular smooth muscle cells, but not human umbilical vein endothelial cells, secreted Ang1. These findings indicate that the Tie2 receptor, PI 3'-kinase, and Akt are crucial elements in the signal transduction pathway leading to endothelial cell survival induced by the paracrine activity of Ang1.     

Integrin {alpha}3, but not {beta}1, regulates islet cell survival and function via PI3K/Akt signaling pathways

β1-integrin is a well-established regulator of β-cell activities; however, the role of its associated α-subunits is relatively unknown. Previously, we have shown that human fetal islet and INS-1 cells highly express α3β1-integrin and that collagens I and IV significantly enhance their survival and function; in addition, blocking β1 function in the fetal islet cells decreased adhesion on collagen I and increased apoptosis. The present study investigates the effect of blocking α3. Using α3 blocking antibody or small interfering RNA, the effects of α3-integrin blockade were examined in isolated human fetal or adult islet cells or INS-1 cells, cultured on collagens I or IV. In parallel, β1 blockade was analyzed in INS-1 cells. Perturbing α3 function in human islet or INS-1 cells resulted in significant decreases in cell function (adhesion, spreading, proliferation and Pdx1 and insulin expression/secretion), primarily on collagen IV. A significant decrease in focal adhesion kinase and ERK1/2 phosphorylation and increased caspase3 cleavage were observed on both collagens. These effects were similar to changes after β1 blockade. Interestingly, only α3 blockade reduced expression of phospho-Akt and members of its downstream signaling cascades (glycogen synthase kinase β and X-linked inhibitor of apoptosis), demonstrating a specific effect of α3 on the phosphatidylinositol 3-kinase/Akt pathway. These results suggest that α3- as well as β1-integrin-extracellular matrix interactions are critical for modulating β-cell survival and function through specialized signaling cascades and enhance our understanding of how to improve islet microenvironments for cell-based treatments of diabetes.     

Netrin-1 is a survival factor during commissural neuron navigation

DCC (Deleted in Colorectal Cancer) is a putative tumor suppressor whose expression is lost in numerous cancers and whose tumor suppressor activity appears to be dependent on its ability to trigger apoptosis when disengaged by its ligand netrin-1. In this sense, netrin-1 is a survival factor that controls tumorigenesis. However, netrin-1 is also the prototypical axon guidance cue and has been shown to orient many neurons or axons, especially commissural axons, during spinal cord development. Here we show that netrin-1 is not only an attractive cue for developing commissural axons but also promotes their survival. In primary neuronal culture, in mice or in chick embryos, netrin-1 inhibits the proapoptotic activity of DCC in developing commissural neurons. Thus, adequate commissural neurons navigation requires both the attractive activity of netrin-1 and the anti-apoptotic function of this cue.