低氧与铁代谢相关蛋白

氧和铁这两种元素对生命活动十分重要. 低氧诱导因子(hypoxia-inducible factors, HIFs)作为转录因子,参与一系列靶基因的表达调控以适应低氧. 铁参与 DNA合成、氧气运输、代谢反应等多种细胞活动,过量游离铁会通过Haber-Weiss或 Fenton反应产生毒性自由基. 细胞通过与铁吸收、存储和利用有关的多种铁代谢相 关蛋白之间的协同作用来维持铁稳态. 与铁稳态相关的一些基因是HIFs的靶基因或 者间接受低氧调控,包括转铁蛋白、转铁蛋白受体、二价金属转运体1、铁调素、膜 铁转运蛋白、血浆铜蓝蛋白、铁蛋白等,而胞内铁浓度的改变能影响HIFs的表达. 本文就低氧与铁代谢相关蛋白的关系,尤其是低氧对铁代谢相关蛋白的调节作一综 述.     

Expression of hypoxia-inducible factors in the peri-implantation mouse uterus is regulated in a cell-specific and ovarian steroid hormone-dependent manner. Evidence for differential function of HIFs during early pregnancy

Increased uterine vascular permeability and angiogenesis are hallmarks of implantation and placentation. These events are profoundly influenced by vascular endothelial growth factor (VEGF). We previously showed that VEGF isoforms and VEGF receptors are expressed in the uterus, suggesting the role of VEGF in uterine vascular permeability and angiogenesis required for implantation and decidualization. We have recently shown that estrogen promotes uterine vascular permeability but inhibits angiogenesis, whereas progesterone stimulates angiogenesis with little effect on vascular permeability. However, the mechanism of differential steroid hormonal regulation of uterine angiogenesis remains unresolved. Oxygen homeostasis is essential for cell survival and is primarily mediated by hypoxia-inducible factors (HIFs). These factors are intimately associated with vascular events and induce VEGF expression by binding to the hypoxia response element in the VEGF promoter. HIFalpha isoforms function by forming heterodimers with the aryl hydrocarbon nuclear translocator (ARNT) (HIF-beta) family members. There is very limited information on the relationship among HIFs, ARNTs, and VEGF in the uterus during early pregnancy, although the role of HIFs in regulating VEGF and angiogenesis in cancers is well documented. Using molecular and physiological approaches, we here show that uterine expression of HIFs and ARNTs does not correlate with VEGF expression during the preimplantation period (days 1-4) in mice. In contrast, their expression follows the localization of uterine VEGF expression with increasing angiogenesis during the postimplantation period (days 5-8). This disparate pattern of uterine HIFs, ARNTs, and VEGF expression on days 1-4 of pregnancy suggests HIFs have multiple roles in addition to the regulation of angiogenesis during the peri-implantation period. Using pharmacological, molecular, and genetic approaches, we also observed that although progesterone primarily up-regulates uterine HIF-1alpha expression, estrogen transiently stimulates that of HIF-2alpha.     

The “Sharp” blade against HIF-mediated metastasis

Hypoxia-inducible factors (HIFs) control cellular adaptation to oxygen deprivation. Cancer cells engage HIFs to sustain their growth in adverse conditions, thus promoting a cellular reprograming that includes metabolism, proliferation, survival and mobility. HIFs overexpression in human cancer biopsies correlates with high metastasis and mortality. A recent report has elucidated a novel mechanism for HIFs regulation in triple-negative breast cancer. Specifically, the basic helix-loop-helix (bHLH), Sharp-1, serves HIF1α to the proteasome and promotes its O₂-indendpendet degradation, counteracting HIF-mediated metastasis. These findings shed light on how HIFs are manipulated during cancer pathogenesis.     

From stem cells to cancer stem cells: HIF takes the stage

Hypoxia, a condition of insufficient oxygen availability, occurs during normal development as well as tumorigenesis. Cellular responses to hypoxia are primarily mediated by hypoxia-inducible factors (HIFs). Recent studies have revealed that dormant hematopoietic stem cells (HSCs) reside within hypoxic regions of the bone marrow and that HIF is a critical player in HSC homeostasis. The functional significance of HIF in maintaining stemness also applies to cancer stem cells in hematological malignancies. These findings indicate that better understanding of the mechanisms underlying HIF functions in stem cells should permit the development of new therapies for tissue regeneration and cancer.     

Deletion of hypoxia-inducible factor prolyl 4-hydroxylase 2 in FoxD1-lineage mesenchymal cells leads to congenital truncal alopecia

Hypoxia-inducible factors (HIFs) induce numerous genes regulating oxygen homeostasis. As oxygen sensors of the cells, the HIF prolyl 4-hydroxylases (HIF-P4Hs) regulate the stability of HIFs in an oxygen-dependent manner. During hair follicle (HF) morphogenesis and cycling, the location of dermal papilla (DP) alternates between the dermis and hypodermis and results in varying oxygen levels for the DP cells. These cells are known to express hypoxia-inducible genes, but the role of the hypoxia response pathway in HF development and homeostasis has not been studied. Using conditional gene targeting and analysis of hair morphogenesis, we show here that lack of Hif-p4h-2 in Forkhead box D1 (FoxD1)-lineage mesodermal cells interferes with the normal HF development in mice. FoxD1-lineage cells were found to be mainly mesenchymal cells located in the dermis of truncal skin, including those cells composing the DP of HFs. We found that upon Hif-p4h-2 inactivation, HF development was disturbed during the first catagen leading to formation of epithelial-lined HF cysts filled by unorganized keratins, which eventually manifested as truncal alopecia. Furthermore, the depletion of Hif-p4h-2 led to HIF stabilization and dysregulation of multiple genes involved in keratin formation, HF differentiation, and HIF, transforming growth factor β (TGF-β), and Notch signaling. We hypothesize that the failure of HF cycling is likely to be mechanistically caused by disruption of the interplay of the HIF, TGF-β, and Notch pathways. In summary, we show here for the first time that HIF-P4H-2 function in FoxD1-lineage cells is essential for the normal development and homeostasis of HFs.     

In silico analyses of Fsf1 sequences, a new group of fungal proteins orthologous to the metazoan sideroblastic anemia-related sideroflexin family

Sideroblastic anemias are pathologies observed in metazoan species characterized by accumulation of iron in the mitochondria (sideroblasts), defective erythropoiesis, and iron overload. Some genes have been associated with sideroblastic anemia, e.g. delta-aminolevulinic acid synthase gene (e-ALAS2). Recently, a new sideroblastic-associated protein family was discovered in metazoans and termed sideroflexin (Sfxn). The metazoan Sfxn family comprises five groups of paralogous proteins, present in mitochondria and whose functions are unknown. Using an in silico approach, we have identified and characterized new sideroflexin sequences from the genomes of different fungal species. An in-depth phylogenetic analysis of these new fungal Sfxn sequences (termed Fsf1p) showed that they form a distinct clade within the metazoan Sfxn family. Hydrophobic cluster analysis and transmembrane topological mapping allowed us to compare conserved regions among Fsf1 and Sfxn proteins. The results indicate that Fsf1 probably belongs to an ancient, mitochondrial group of proteins, necessary to maintain the homeostasis of iron within this organelle.     

Apoptosis in pre-Bilaterians: <Emphasis Type="Italic">Hydra</Emphasis> as a model

Hydra is a member of the ancient metazoan phylum Cnidaria and is an especially well investigated model organism for questions of the evolutionary origin of metazoan processes. Apoptosis in Hydra is important for the regulation of cellular homeostasis under different conditions of nutrient supply. The molecular mechanisms leading to apoptosis in Hydra are surprisingly extensive and comparable to those in mammals. Genome wide sequence analysis has revealed the presence of large caspase and Bcl-2 families, the apoptotic protease activating factor (APAF-1), inhibitors of apoptotic proteases (IAPs) and components of a putative death receptor pathway. Regulation of apoptosis in Hydra may involve BH-3 only proteins and survival pathways, possibly including insulin signalling.     

The Roles of Hypoxia-Inducible Factors in Regulating Neural Stem Cells Migration to Glioma Stem Cells and Determinating Their Fates

The mortality of patients with malignant gliomas remains high despite the advancement in multi-modal therapy including surgery, radio- and chemotherapy. Glioma stem cells (GSCs), sharing some characteristics with normal neural stem cells (NSCs), contribute to the cellular origin for primary gliomas and the recurrence of malignant gliomas after current conventional therapy. Accordingly, targeting GSCs proves to be a promising avenue of therapeutic intervention. The specific tropism of NSCs to GSCs provides a novel platform for targeted delivery of therapeutic agents. Tropism and mobilization of NSCs are enhanced by hypoxia through upregulating chemotactic cytokines and activating several signaling pathways. Moreover, hypoxia-inducible factors (HIFs) produced under hypoxic microenvironment of the stem cell niche play critical roles in the growth and stemness phenotypes regulation of both NSCs and GSCs. However, the definite cellular and molecular mechanisms of HIFs involvement in the process remain obscure. In this review, we focus on the pivotal roles of HIFs in migration of NSCs to GSCs and potential roles of HIFs in dictating the fates of migrated NSCs and targeted GSCs.     

Physiology and pathology of endosome-to-Golgi retrograde sorting

Bidirectional traffic between the Golgi apparatus and the endosomal system sustains the functions of the trans-Golgi network (TGN) in secretion and organelle biogenesis. Export of cargo from the TGN via anterograde trafficking pathways depletes the organelle of sorting receptors, processing proteases, SNARE molecules, and other factors, and these are subsequently retrieved from endosomes via the retrograde pathway. Recent studies indicate that retrograde trafficking is vital to early metazoan development, nutrient homeostasis, and for processes that protect against Alzheimer's and other neurological diseases.     

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

Mitochondria are essential cellular organelles that are involved in regulating cellular energy, metabolism, survival, and proliferation. To some extent, cancer is a genetic and metabolic disease that is closely associated with mitochondrial dysfunction. Hypoxia-inducible factors (HIFs), which are major molecules that respond to hypoxia, play important roles in cancer development by participating in multiple processes, such as metabolism, proliferation, and angiogenesis. The Warburg phenomenon reflects a pseudo-hypoxic state that activates HIF-1α. In addition, a product of the Warburg effect, lactate, also induces HIF-1α. However, Warburg proposed that aerobic glycolysis occurs due to a defect in mitochondria. Moreover, both HIFs and mitochondrial dysfunction can lead to complex reprogramming of energy metabolism, including reduced mitochondrial oxidative metabolism, increased glucose uptake, and enhanced anaerobic glycolysis. Thus, there may be a connection between HIFs and mitochondrial dysfunction. In this review, we systematically discuss the crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Above all, the stability and activity of HIFs are closely influenced by mitochondrial dysfunction related to tricarboxylic acid cycle, electron transport chain components, mitochondrial respiration, and mitochondrial-related proteins. Furthermore, activation of HIFs can lead to mitochondrial dysfunction by affecting multiple mitochondrial functions, including mitochondrial oxidative capacity, biogenesis, apoptosis, fission, and autophagy. In general, the regulation of tumorigenesis and development by HIFs and mitochondrial dysfunction are part of an extensive and cooperative network.Subject terms: Cancer metabolism, Cancer microenvironment     

Apoptosis: lessons from in vitro systems

Although apoptosis is a major factor in metazoan morphogenesis and tissue homeostasis, its underlying biochemical mechanisms are poorly understood. This is now beginning to change as cell-free systems for the study of apoptosis start to reveal some of the activities involved. As suggested by earlier genetic analyses, a proteinase with properties resembling those of the interleukin-1-beta-converting enzyme (ICE) has been shown to initiate the apoptotic cascade in vitro. Curiously, results obtained with the cell-free systems suggest that essential downstream effectors of the apoptotic response may be intrinsic components of healthy nuclei.