RESUMEN
In the classical renin-angiotensin system, circulating ANG II mediates growth stimulatory and hemodynamic effects through the plasma membrane ANG II type I receptor, AT1. ANG II also exists in the intracellular space in some native cells, and tissues and can be upregulated in diseases, including hypertension and diabetes. Moreover, intracellular AT1 receptors can be found associated with endosomes, nuclei, and mitochondria. Intracellular ANG II can function in a canonical fashion through the native receptor and also in a noncanonical fashion through interaction with alternative proteins. Likewise, the receptor and proteolytic fragments of the receptor can function independently of ANG II. Participation of the receptor and ligand in alternative intracellular pathways may serve to amplify events that are initiated at the plasma membrane. We review historical and current literature relevant to ANG II, compared with other intracrines, in tissue culture and transgenic models. In particular, we describe a new transgenic mouse model, which demonstrates that intracellular ANG II is linked to high blood pressure. Appreciation of the diverse, pleiotropic intracellular effects of components of the renin-angiotensin system should lead to alternative disease treatment targets and new therapies.
Asunto(s)
Angiotensina II/fisiología , Núcleo Celular/fisiología , Citoplasma/fisiología , Animales , Modelos Animales de Enfermedad , Hipertensión/fisiopatología , Técnicas In Vitro , Ratones , Ratones Transgénicos , Receptor de Angiotensina Tipo 1/fisiología , Sistema Renina-Angiotensina/fisiologíaRESUMEN
Several transmembrane receptors are documented to accumulate in nuclei, some as holoreceptors and others as cleaved receptor products. Our prior studies indicate that a population of the 7-transmembrane angiotensin type-1 receptor (AT(1)R) is cleaved in a ligand-augmented manner after which the cytoplasmic, carboxy-terminal cleavage fragment (CF) traffics to the nucleus. In the present report, we determine the precise cleavage site within the AT(1)R by mass spectrometry and Edman sequencing. Cleavage occurs between Leu(305) and Gly(306) at the junction of the seventh transmembrane domain and the intracellular cytoplasmic carboxy-terminal domain. To evaluate the function of the CF distinct from the holoreceptor, we generated a construct encoding the CF as an in-frame yellow fluorescent protein fusion. The CF accumulates in nuclei and induces apoptosis in CHO-K1 cells, rat aortic smooth muscle cells (RASMCs), MCF-7 human breast adenocarcinoma cells, and H9c2 rat cardiomyoblasts. All cell types show nuclear fragmentation and disintegration, as well as evidence for phosphotidylserine displacement in the plasma membrane and activated caspases. RASMCs specifically showed a 5.2-fold increase (P < 0.001) in CF-induced active caspases compared with control and a 7.2-fold increase (P < 0.001) in cleaved caspase-3 (Asp174). Poly(ADP-ribose)polymerase was upregulated 4.8-fold (P < 0.001) in CF expressing cardiomyoblasts and colocalized with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). CF expression also induces DNA laddering, the gold-standard for apoptosis in all cell types studied. CF-induced apoptosis, therefore, appears to be a general phenomenon as it is observed in multiple cell types including smooth muscle cells and cardiomyoblasts.
Asunto(s)
Apoptosis , Caspasas/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular , Núcleo Celular/metabolismo , Células Cultivadas , Humanos , Etiquetado Corte-Fin in Situ , Datos de Secuencia Molecular , Poli(ADP-Ribosa) Polimerasas/metabolismo , Ratas , Regulación hacia ArribaRESUMEN
The present study tested the hypothesis that intrarenal adenoviral transfer of an intracellular cyan fluorescent fusion of angiotensin II (ECFP/ANG II) selectively in proximal tubules of the kidney increases blood pressure by activating AT(1) (AT(1a)) receptors. Intrarenal transfer of ECFP/ANG II was induced in the superficial cortex of rat and mouse kidneys, and the sodium and glucose cotransporter 2 (sglt2) promoter was used to drive ECFP/ANG II expression selectively in proximal tubules. Intrarenal transfer of ECFP/ANG II induced a time-dependent, proximal tubule-selective expression of ECFP/ANG II in the cortex, which peaked at 2 wk and was sustained for 4 wk. ECFP/ANG II expression was low in the glomeruli and the entire medulla and was absent in the contralateral kidney or extrarenal tissues. At its peak of expression in proximal tubules at day 14, ANG II was increased by twofold in the kidney (P < 0.01) and more than threefold in proximal tubules (P < 0.01), but remained unchanged in plasma or urine. Systolic blood pressure was increased in ECFP/ANG II-transferred rats by 28 ± 6 mmHg (P < 0.01), whereas fractional sodium excretion was decreased by 20% (P < 0.01) and fractional lithium excretion was reduced by 24% (P < 0.01). These effects were blocked by losartan and prevented in AT(1a) knockout mice. Transfer of a scrambled ECFP/ANG IIc had no effects on blood pressure, kidney, and proximal tubule ANG II, or sodium excretion. These results provide evidence that proximal tubule-selective transfer of an intracellular ANG II fusion protein increases blood pressure by activating AT(1a) receptors and increasing sodium reabsorption in proximal tubules.
Asunto(s)
Angiotensina II/biosíntesis , Presión Sanguínea , Técnicas de Transferencia de Gen , Proteínas Fluorescentes Verdes/biosíntesis , Hipertensión/metabolismo , Túbulos Renales Proximales/metabolismo , Adenoviridae/genética , Angiotensina II/sangre , Angiotensina II/genética , Angiotensina II/orina , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Células Cultivadas , Modelos Animales de Enfermedad , Vectores Genéticos , Proteínas Fluorescentes Verdes/sangre , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/orina , Hipertensión/genética , Hipertensión/fisiopatología , Hipertensión/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Natriuresis , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/deficiencia , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Proteínas Recombinantes de Fusión/biosíntesis , Factores de Tiempo , Transducción Genética , Transfección , Regulación hacia Arriba , MicciónRESUMEN
In recent years the actions of intracellular-acting, extracellular signaling proteins/peptides (intracrines) have become increasingly defined. General principles of intracrine action have been proposed. Mitochondria represent one locus of intracrine action, and thus far, angiotensin II, transforming growth factor-beta, growth hormone, atrial natriuretic peptide, Wnt 13, stanniocalcin, other renin-angiotensin system components, and vascular endothelial-derived growth factor, among others, have been shown to be mitochondria-localizing intracrines. The implications of this mitochondrial intracrine biology are discussed.
Asunto(s)
Angiotensina II/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Mitocondrias/metabolismo , Transducción de Señal , AnimalesRESUMEN
Proteins that bind to the intracellular expanses, particularly cytoplasmic tail regions, of heptahelical integral membrane receptors are of particular interest in that they can mediate or modulate trafficking or intracellular signaling. In an effort to distinguish new proteins that might promote angiotensin II type 1 (AT(1)) receptor intracellular events, we screened a yeast 2-hybrid mouse brain library with the rat AT(1A) receptor (AT(1)R) carboxyl terminus and identified GABARAP, a protein involved in intracellular trafficking of the GABA(A) receptor, as a binding partner for the AT(1)R. Interaction of GABARAP with the AT(1)R carboxyl terminus was further substantiated using GST pull-down assays, and binding of the full-length tagged AT(1)R to GABARAP was verified using coimmunoprecipitation. Bioluminescence resonance energy transfer assays further confirmed specific interaction of GABARAP with AT(1)R. Moreover, GABARAP clearly increased the steady-state level of plasma membrane-associated AT(1)R in PC-12 cells. Cotransfection of GABARAP with an AT(1)R fluorescent fusion protein increased PC-12 cell surface expression of the AT(1)R more than 6-fold when standardized to the level of intracellular expression. Furthermore, GABARAP overexpression in CHO-K1 cells engineered to express AT(1)R increased angiotensin II binding sites 3.7-fold and angiotensin II-induced phospho-extracellular signal-regulated kinase 1/2 and cellular proliferation significantly over levels obtained with AT(1)R overexpression alone. In addition, small interfering RNA-mediated knockdown of GABARAP reduced the steady-state levels of the AT(1)R fluorescent fusion protein by 43% and its cell surface expression by 84%. Immunoblot analyses confirmed the quantitative image data. We conclude that GABARAP binds to and promotes trafficking of the AT(1)R to the plasma membrane.
Asunto(s)
Membrana Celular/metabolismo , Proteínas del Citoesqueleto/fisiología , Proteínas de la Membrana/fisiología , Receptor de Angiotensina Tipo 1/fisiología , Animales , Proteínas Reguladoras de la Apoptosis , Células CHO/metabolismo , Células COS/metabolismo , División Celular/efectos de los fármacos , Chlorocebus aethiops , Cricetinae , Cricetulus , Proteínas del Citoesqueleto/aislamiento & purificación , Losartán/farmacología , Proteínas de la Membrana/aislamiento & purificación , Ratones , Proteínas Asociadas a Microtúbulos , Células PC12/metabolismo , Unión Proteica , Mapeo de Interacción de Proteínas , Transporte de Proteínas , Interferencia de ARN , Ensayo de Unión Radioligante , Ratas , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Proteínas Recombinantes de Fusión/metabolismo , TransfecciónRESUMEN
Some extracellular-signaling peptides also at times function within the intracellular space. We have termed these peptides intracrines and have argued that intracrine function is associated with a wide variety of peptides/proteins including hormones, growth factors, cytokines, enzymes, and DNA-binding proteins among others. Here we consider the possibility that intracrines participate in the related phenomena of senescence, apoptosis, and stem cell regulation of tissue biology. Based on this analysis, we also suggest that the concept of intracrine action be expanded to include possible regulatory peptide transfer via exosomes/microvesicles and possibly by nanotubes. Moreover, the process of microvesicular and nanotube transfer of peptides and other biologically relevant molecules, which we inclusively term laterality, is explored. These notions have potentially important therapeutic implications, including implications for the therapy of cardiovascular disease.
Asunto(s)
Apoptosis/fisiología , Enfermedades Cardiovasculares/patología , Senescencia Celular/fisiología , Péptidos y Proteínas de Señalización Intracelular/fisiología , Células Madre/citología , Células Madre/fisiología , Animales , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Humanos , Transducción de Señal/fisiologíaRESUMEN
Intracrines are extracellular signaling peptide factors that can act in the intracellular space after either internalization or retention in the cells that synthesize them. They are structurally diverse and include hormones, growth factors, enzymes, DNA-binding proteins, and other peptide moieties. We have suggested principles of intracrine action and have applied those principles to forms of cellular and tissue differentiation, hormonal responsiveness, and memory. Moreover, recent findings make clear that some currently available pharmaceuticals act via the alteration of intracrine function. Thus, the beginnings of an intracrine pharmacology are at hand and we here review principles applicable to the design of such agents. The intracrine pharmacology of the renin-angiotensin system, angiogenesis, and stem cell development is discussed.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Diferenciación Celular/fisiología , Humanos , Péptidos y Proteínas de Señalización Intracelular/fisiología , Modelos Biológicos , Neovascularización Fisiológica/efectos de los fármacos , Neovascularización Fisiológica/fisiología , Sistema Renina-Angiotensina/fisiología , Transducción de Señal/fisiologíaRESUMEN
Angiogenesis, in most cases, is a requirement for tumor growth beyond a diameter of a few millimeters and is, therefore, a major target for cancer therapy. The intracellular actions of certain extracellular signaling proteins (intracrines) have been reported, and it is clear that intracrines such as vascular endothelial growth factor, basic fibroblast growth factor, angiogenin, angiotensin, and endothelin, among others, are involved in angiogenesis. We have proposed that intracrine networks play an important role in angiogenesis, and have suggested that very similar intracrine networks exist in some tumor cells. These notions have implications for the development of anti-angiogenesis therapies because they suggest that the inhibition of intracellular intracrine trafficking pathways may be an effective therapeutic target. Here the participation and regulation of intracrines in angiogenesis is explored, as are the actions of various anti-angiogenic factors.
Asunto(s)
Inhibidores de la Angiogénesis/fisiología , Proteínas Angiogénicas/fisiología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/terapia , Inhibidores de la Angiogénesis/uso terapéutico , Proteínas Angiogénicas/antagonistas & inhibidores , Proteínas Angiogénicas/uso terapéutico , Animales , HumanosRESUMEN
The intracellular actions of peptide hormones, growth factors, as well as of extracellular-signaling enzymes and DNA-binding proteins, either within target cells or within their cells of synthesis has been called intracrine action. Although these intracrine moieties are structurally diverse, they share certain characteristics of synthesis and function. This has given rise to the development of a theory of intracrine action which permits testable predictions to be made regarding the functioning of these peptides/proteins. Here the intracrine hypothesis is briefly described and then recent experimental findings which bear on predictions made earlier on the basis of the theory are discussed. These findings provide new support for the intracrine hypothesis.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Modelos Biológicos , Transducción de Señal/fisiología , Animales , Sustancias de Crecimiento/metabolismo , Humanos , Hormonas Peptídicas/metabolismo , Precursores de Proteínas/metabolismoRESUMEN
Many extracellular signaling proteins act within their cells of synthesis and/or in target cells after internalization. This type of action is called intracrine and it plays a role in diverse biological processes. The mechanisms of intracrine intracellular action are becoming clear thanks to the application of modern techniques of molecular biology. Here, progress in this area is reviewed. In particular the intracrine biology of angiotensin II is discussed.
Asunto(s)
Angiotensina II/metabolismo , Espacio Intracelular/metabolismo , Animales , Humanos , Ratones , Ratones TransgénicosRESUMEN
We have previously shown that oligonucleotides designed to bind in triplex fashion to a specific p53 binding site homology inhibit the proliferation of colon cancer cells in vitro. The present study was designed to extend these observations in an in vivo model. HCT 116 human colon carcinoma cells were injected subcutaneously into Ncr nude mice and tumors formed at one to two weeks. Tumors were injected daily for 14 days with either triplex forming oligonucleotide (Hoog 1), a scrambled Hoog 1 oligonucleotide (Hoog3) as control, or vehicle. Tumor size was measured twice weekly. Active triplex forming oligonucleotide (Hoog1) reduced tumor size in comparison to either control oligonucleotide (Hoog3) or vehicle. Tumor sizes in the three groups were significantly different (P < 0.001). Student Newman Keuls test shows statistically significant differences between the experimental group and each of the control and vehicle groups (P < 0.05). A triplex forming oligonucleotide directed at a p53 consensus binding site reduces tumor growth suggesting a novel method of tumor inhibition.
Asunto(s)
Neoplasias del Colon/terapia , ADN , Oligonucleótidos/farmacología , Animales , Sitios de Unión , Línea Celular Tumoral , Neoplasias del Colon/patología , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Factores de Tiempo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: We previously identified the binding of the chaperone protein gamma-aminobutyric acid receptor-associated protein (GABARAP) to a sequence on the carboxy-terminus of the angiotensin II AT1 receptor (AT1R) and showed that this binding enhances AT1R trafficking to the cell surface as well as angiotensin signaling. METHODS: In this study, we treated sodium-depleted mice with decoy peptides consisting either of a fusion of the cell-penetrating peptide penetratin and the GABARAP/AT1R binding sequence or penetratin fused to a mutated AT1R sequence. We used telemetry to measure blood pressure. RESULTS: Systolic and diastolic pressure fell during the 24 hours following decoy peptide injection but not after control peptide injection. Active cell-penetrating decoy peptide decreased 24-hour average systolic blood pressure from 129.8 ± 4.7 mmHg to 125.0 ± 6.0 mmHg (mean ± standard deviation). Diastolic blood pressure fell from 99.0 ± 7.1 mmHg to 95.0 ± 9.2 mmHg (n=5). Administration of the control peptide raised systolic blood pressure from 128.7 ± 1.3 mmHg to 131.7 ± 2.9 mmHg and diastolic pressure from 93.9 ± 4.5 mmHg to 95.9 ± 4.2 mmHg (n=5). The decreases in both systolic and diastolic blood pressure after active peptide administration were statistically significant compared to control peptide administration (P<0.05, two-tailed Wilcoxon rank-sum test). CONCLUSION: These results indicate the physiological and potentially therapeutic relevance of inhibitors of GABARAP/AT1R binding.
RESUMEN
BACKGROUND: Several studies suggest that extracellular angiotensin can upregulate renin and angiotensinogen (AGT). We have shown that enhanced cyan fluorescent protein/angiotensin II (ECFP/AngII) transgenic mice, in which AngII is fused downstream of ECFP and regulated by the mouse metallothionein housekeeping gene, possess elevated blood pressure and kidney thrombotic microangiopathy. The present study evaluated the effect of intracellular AngII on AGT messenger RNA (mRNA) and protein levels in ECFP/AngII transgenic mice. METHODS: The traditional guanidinium thiocyanate method was used to extract total mRNA. Proteins were extracted by homogenization in a tissue extraction reagent buffer. Northern blots for AGT mRNA and an 18S ribosomal RNA control were performed. Immunoblots for AGT protein levels with actin and tubulin controls were evaluated. RESULTS: Northern blot densitometry showed liver mRNA levels an average of 12-fold greater than levels in the brain or kidney in both Lines A and D (different copies of the transgene) with no quantifiable differences between wild-type (WT) and homozygous (HO) transgenic mice. Immunoblots showed liver AGT protein levels 3.2-fold greater than levels in the brain or kidney, with no differences observed between WT and HO transgenic mice. CONCLUSION: ECFP/AngII transgene expression does not alter AGT mRNA or protein levels in major organs (kidney, liver, and brain) of transgenic mice. The altered blood pressure and kidney thrombosis observed in these transgenic mouse lines are not the result of increased intracellular AGT synthesis and resultant increases in free extracellular AngII. This finding is consistent with our published studies that indicate no increase in circulating AngII by radioimmunoassay.
RESUMEN
BACKGROUND: Our previous published studies have established the γ-aminobutyric acid (GABA) receptor-associated protein (GABARAP) as a trafficking protein for the angiotensin II type 1A receptor (AT(1)R). GABARAP overexpression increases both AT(1)R protein accumulation and translocation to the plasma membrane. The present study examined the inhibitory effects of decoy peptides on receptor expression and plasma membrane accumulation. The decoy peptides correspond to the AT(1)R cytoplasmic domain located immediately proximal to the 7th transmembrane domain, a region implicated in GABARAP binding. This competitive binding study was designed as a first step toward evaluating the GABARAP:AT(1)R binding interface as a target for reducing AT(1)R trafficking to the plasma membrane. METHODS: AT(1)R and GABARAP plasmids were transfected into mammalian cell lines simultaneously with cell-penetrating peptides (CPPs). CPP-1 and CPP-2 consist of the penetratin (pANT(43-58)) CPP with downstream fusions of GKKFKKYFLQL (AT(1)R) and GKKFEEAFLQL (AT(1)R-mutant) amino acids, respectively. CPP-3 consists of the HIV TAT(48-60) CPP with GKKFKKYFLQL (AT(1)R) fused downstream. Western blotting, signal transduction studies, and 3D deconvolution microscopy experiments were employed. RESULTS: Immunoblot analyses and live cell deconvolution microscopy demonstrated that inhibitory (but not control) peptides completely blocked GABARAP-induced intracellular AT(1)R accumulation and cell surface accumulation. GABARAP also stimulated angiotensin II-mediated phospho-ERK1/2 induction by ~ fivefold. This activation was, similarly, quantitatively blocked by the inhibitory peptides. CONCLUSIONS: Cell-penetrating decoy peptides which were designed to block the AT(1)R:GABARAP interaction, effectively reduced AT(1)R intracellular accumulation and cell-surface trafficking and signaling. The binding interaction site between AT(1)R and GABARAP represents a potential therapeutic target.
Asunto(s)
Membrana Celular/metabolismo , Péptidos de Penetración Celular/farmacología , Proteínas del Citoesqueleto/farmacología , Proteínas de la Membrana/farmacología , Receptor de Angiotensina Tipo 1/biosíntesis , Animales , Proteínas Reguladoras de la Apoptosis , Células COS , Chlorocebus aethiops , Ratones , Proteínas Asociadas a Microtúbulos , Células PC12 , Ratas , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Receptor de Angiotensina Tipo 1/metabolismoRESUMEN
Over the past 3 decades it has become clear that a large number of extracellular signaling proteins/peptides also act in the intracellular space. These factors are termed intracrines and, although diverse in structure, they share a variety of functional features. In recent years, attention has increasingly turned to identifying the intracellular mechanisms of intracrine action and their implications for human disorders, such as cancer and cardiovascular disease. Perhaps not surprisingly, some intracrines have been shown to bind to and activate their cognate receptors located on intracellular membranes, such as the nuclear envelope. Here we discuss known intracrine actions and argue that mechanisms distinct from membrane receptor activation (that is, "noncanonical" actions) are often operative and physiologically relevant. These actions, we argue, expand our understanding of peptide signaling in important ways. Moreover, an appreciation of noncanonical intracrine functionality informs our understanding of the major effector protein of the renin-angiotensin system, angiotensin II, as well as other hormones operative in cardiovascular biology.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/fisiología , Angiotensina II/fisiología , Comunicación Celular/fisiología , Factores de Crecimiento de Fibroblastos/fisiología , Glicoproteínas/fisiología , Proteínas de Homeodominio/fisiología , Humanos , Espacio Intracelular/fisiología , Proteína Relacionada con la Hormona Paratiroidea/fisiología , Receptores Acoplados a Proteínas G/fisiología , Transducción de Señal/fisiologíaRESUMEN
OBJECTIVE: GABARAP, a small (117 aa) trafficking protein, binds to the C-terminal, cytoplasmic domain of rat angiotensin type-1A receptor (AT(1)R), the predominant effector of the octapeptide angiotensin II (Ang II) (Cook et al., Circ. Res. 2008;102:1539-47). The objectives of this study were to map the interaction domains of GABARAP and AT(1)R, to determine the effect of GABARAP association on AT(1)R signaling activity, and to determine the importance of post-translational processing of GABARAP on accumulation of AT(1)R on the plasma membrane and its signaling function. RESULTS: Deletion analysis identified two regions within GABARAP necessary for interaction with AT(1)R in yeast two-hybrid assays: 1) a domain comprised of residues 32-51 that is nearly identical to that involved in binding and intracellular trafficking of the GABA(A) receptor and 2) a domain encompassing the C-terminal 21 aa. The GABARAP interaction domain of AT(1)R was delimited to the 15 aa immediately downstream of the last membrane spanning region. Overexpression of GABARAP in rat adrenal pheochromocytoma PC-12 cells increased the cell-surface expression of AT(1)R and Ang II-dependent activation of the cAMP signaling pathway. Residues within AT(1)R necessary for these responses were identified by mutational analysis. In PC-12 cells, GABARAP was constitutively and quantitatively cleaved at the C-terminus peptide bond and this cleavage was prevented by mutation of Gly(116). Wild-type GABARAP and the G116A mutant were, however, equally effective in stimulating AT(1)R surface expression and signaling activity. CONCLUSIONS: GABARAP and AT(1)R interact through discrete domains and this association regulates the cell-surface accumulation and, consequently, ligand-induced function of the receptor. Unlike that observed with the GABA(A) receptor, this regulation is not dependent on C-terminal processing and modification of GABARAP.
Asunto(s)
Proteínas Asociadas a Microtúbulos/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Transducción de Señal/fisiología , Secuencia de Aminoácidos , Angiotensina II/genética , Angiotensina II/metabolismo , Animales , Proteínas Asociadas a Microtúbulos/genética , Células PC12 , Unión Proteica/fisiología , Estructura Terciaria de Proteína/fisiología , Transporte de Proteínas/fisiología , Ratas , Receptor de Angiotensina Tipo 1/genética , Eliminación de SecuenciaRESUMEN
Intracrine peptides and proteins participate in the regulation of adult and pleuripotential embryonic-like stem cells. Included among these factors are VEGF, dynorphin, the readthrough form of acetylcholinesterase, Oct3/4, Pdx-1, Pax-6, and high-mobility group protein B1, among others. In some cases, the establishment of intracrine feedback loops can be shown to be relevant to this regulation, consistent with previously proposed principles of intracrine action. Here the role of intracrines in stem cell regulation is reviewed, with particular attention to the intracrine regulation of cardiac stem cells. The reprogramming of cells to restore the pleuripotent phenotype and the possible role of stem/progenitor cells in neoplasia are also discussed.
Asunto(s)
Diferenciación Celular , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Transducción de Señal , Células Madre/metabolismo , Adulto , Células Madre Adultas/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular , Proteínas de Unión al ADN/metabolismo , Retroalimentación Fisiológica , Proteínas de Homeodominio/metabolismo , Humanos , Miocitos Cardíacos/metabolismo , Células Madre Neoplásicas/metabolismo , Fenotipo , Células Madre Pluripotentes/metabolismo , Transducción de Señal/efectos de los fármacos , Células Madre/efectos de los fármacos , Factores de Transcripción/metabolismoRESUMEN
The ability to communicate with the environment and respond to changes--particularly those of an adverse nature--within that environment is critical for cell function and survival. A key component of the overall cellular stress response includes adjustments in the gene expression program in favor of proteins that manifest activities capable of frustrating and eventually eliminating the molecular constituents of the stress condition. One protein providing such cytoprotective activity is heme oxygenase-1 (HO-1), an enzyme that catalyzes the rate-limiting reaction in heme catabolism (i.e., the oxidative cleavage of b-type heme molecules to yield equimolar quantities of biliverdin IXalpha, carbon monoxide, and iron). Because of the potent antioxidant, anti-inflammatory, and signaling properties of the reaction products, the HO-1 gene (hmox1) is frequently activated under a variety of cellular stress conditions. Cells use multiple signaling pathways and transcription factors to fine-tune their response to a specific circumstance. Among these factors, members of the heat-shock factor, nuclear factor-kappaB, nuclear factor-erythroid 2, and activator protein-1 families are arguably the most important regulators of the cellular stress response in vertebrates. Although there is functional overlap between individual families, each broadly regulates different aspects of the cellular stress response and thus, with some exceptions, modulates the expression of different sets of targets genes. To the best of our knowledge, hmox1 is unique in that it is proposed to be directly regulated by all four of these stress-responsive transcription factors. In this article we provide a review and analysis of the data supporting this proposition.