Correction: Alfaro-Arnedo et al. IGF1R as a Potential Pharmacological Target in Allergic Asthma. Biomedicines 2021, 9, 912

Correction to Biomedicines 2021, 9(8), 912.Depto. de FisiologíaFac. de MedicinaTRUEpu

Differential ErbB receptor expression and intracellular signaling activity in lung adenocarcinomas and squamous cell carcinomas

EGFR (ErbB1) and ErbB2 receptors stimulate several intracellular signaling pathways in non-small-cell lung cancer (NSCLC). Adenocarcinomas (AC) and squamous cell carcinomas (SCC) are NSCLC subtypes with distinct clinico-pathological features, and responses to ErbB-targeted inhibitors treatment. To evaluate the causes of these differences, tissue microarrays with samples from NSCLC patients (189 AC and 56 SCC) were used to study EGFR and ErbB2 expression and phospho-activation of ERK1/2, AKT, STAT3 and SRC ErbB-mediators by immunohistochemistry and Western blot, and EGFR and ErbB2 gene amplification by FISH. EGFR expression was higher in SCC than in AC (P < 0.001), while ErbB2 showed similar low levels. Phosphorylated (p) ERK, pAKT, pSTAT3 and pSRC levels were prevalent in AC (P ≤ 0.002). EGFR levels and signaling mediators activation were differentially associated with each of the pathologies. Whereas in AC the expression and amplification of EGFR were linked to AKT activation (P ≤ 0.050), in SCC its expression was correlated with pSTAT3 (P = 0.024). In addition, pSTAT3 was correlated with pERK and pAKT only in AC (P ≤ 0.045). Biomarker levels were also differentially associated with the clinico-pathologic variables. In AC, EGFR and pSRC increasing scores correlated with female sex and the smoking habit (P ≤ 0.008), while ErbB2 amplification increased with advanced age and tumor stage (P ≤ 0.047), and pERK1/2 and pSTAT3 levels correlated with early tumor stage (P ≤ 0.045). In SCC, EGFR amplification was stronger in younger patients (P = 0.013), pERK1/2 in the older ones (P = 0.050), and pSTAT3 amplification was stronger in women (P = 0.001). These data support that AC and SCC lung tumors are distinct entities at the molecular level, and that their signaling status in combination with their clinico-pathologic variables may be considered for differential targeted therapies. © 2008 Elsevier Ireland Ltd. All rights reserved.This study was supported in part by a grant from the Junta de Castilla y León, Spain (Grant number SAN191/SA1206), and in part by the Fundación Solórzano, Universidad de Salamanca, Spain (Grants to 2004 and 2005).Peer Reviewe

Delayed inner ear maturation and neuronal loss in postnatal Igf-1-deficient mice

12 pages, 7 figures, 2 tables.Insulin-like growth factor-1 (IGF-1) has been shown to play a key role during embryonic and postnatal development of the CNS, but its effect on a sensory organ has not been studied in vivo. Therefore, we examined cochlear growth, differentiation, and maturation in Igf-1 gene knock-out mice at postnatal days 5 (P5), P8, and P20 by using stereological methods and immunohistochemistry. Mutant mice showed reduction in size of the cochlea and cochlear ganglion. An immature tectorial membrane and a significant decrease in the number and size of auditory neurons were also evident at P20. IGF-1-deficient cochlear neurons showed increased caspase-3-mediated apoptosis, along with aberrant expression of the early neural markers nestin and Islet 1/2. Cochlear ganglion and fibers innervating the sensory cells of the organ of Corti presented decreased levels of neurofilament and myelin P(0) in P20 mouse mutants. In addition, an abnormal synaptophysin expression in the somata of cochlear ganglion neurons and sensory hair cells suggested the persistence of an immature pattern of synapses distribution in the organ of Corti of these animals. These results demonstrate that lack of IGF-1 in mice severely affects postnatal survival, differentiation, and maturation of the cochlear ganglion cells and causes abnormal innervation of the sensory cells in the organ of Corti.This work was supported by Dirección General de Investigación y Desarrollo (Spain) Grants PM96.0075 and PM99–0111 (I.V.-N.) and PM97.0143 (F.d.P.) and Autonomous Community of Madrid grant CAM 08.5/0023/98 (C.A.). The fellowships to G.C. and C.F.-M. were awarded by the Ministerio de Educación y Cultura (Spain).Peer reviewe

Increased leptin and white adipose tissue hypoplasia are sexually dimorphic in Lif null/Igf-I haploinsufficient mice

We previously showed cooperation of leukemia inhibitory factor (LIF) and insulin-like growth factor I (IGF-I) during development. Mice doubly deficient in LIF and IGF-I died at birth. We now analyze the possible combined influence of both factors on postnatal growth. The haploinsufficiency of the Igf-I gene on a Lif null background caused a marked reduction in body mass index and white adipose tissue only in female mice. These animals had increased leptin, increased serum IGF-I and apparent substitution of white adipose tissue by brown adipose tissue. The complex interrelationships between LIF and IGF-I in regulating weight thus involve sexually dimorphic effects on adipose tissue differentiation and circulating leptinThis study was funded by Grants BMC 2001-2132 from the MCYT and 01/0952 from FIS, Spain to F.deP., BMC2002-01680 from the MCYT to J.G.P. and NIH/NDDK-DK54862 to V.C.Peer Reviewe

Eficacia de la deleción condicional del receptor 1 de IGFs (Igf1r) inducida por tamoxifeno en ratones transgénicos adultos: efecto en diferentes órganos y en el epitelio pulmonar

Resumen del póster presentado al XXXVI Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Madrid del 3 al 6 de septiembre de 2013.Los IGFs (Insulin Like Growth Factors), IGF1 e IGF2, regulan la proliferación, diferenciación y supervivencia de las células que expresan su receptor de tipo 1, el IGF1R. IGF1R es un receptor tirosín-kinasa que a través de los IRSs, señaliza sobre todo por la ruta de PI3K/AKT, pero también por RAS/MAPK y STATs. Regula el crecimiento y la homeostasis del organismo, afectando a todos los órganos, aunque también ejerce funciones más específicas dependiendo del momento y tipo celular, sobre todo como promitótico y anti-apoptótico. En el adulto activa el crecimiento y remodelación tisular, y posee acciones neuro-, cardio-, vasculo- y ótico-protectoras. Está implicado en desarrollo del pulmón, en su regeneración tras una lesión y en enfermedades pulmonares. Los ratones deficientes de IGF1R se mueren al nacer por fallo respiratorio con un gran retraso del crecimiento (45%). Aunque se han generado múltiples ratones mutantes condicionales de Igf1r usando el sistema Cre/loxP, no se ha descrito ningún modelo murino con deficiencia de IGF1R generalizada en adultos. Con este objetivo hemos generado ratones con deleción inducible de Igf1r cruzando transgénicos con expresión de Cre activada por tamoxifeno (UBC-CreERT2) con mutantes Igf1rfl. Administrando tamoxifeno a los ratones doble transgénicos (Cre-ERT2Tg/+; Igf1rfl/fl) de un mes de edad demostramos que cuatro semanas después la deleción de Igf1r es efectiva en distintos tejidos, incluido pulmón, cóclea y testículo. Esta deleción genera un retraso del crecimiento generalizado en el animal, afectando significativamente a testículo y cerebro. En el pulmón, la deficiencia de IGF1R genera pérdida de células de Clara en el epitelio bronquiolar terminal. Se mostrarán y discutirán éstos y otros resultados preliminares.Peer Reviewe

Mice lacking IGF-I and LIF have motoneuron deficits in brain stem nuclei

We analyzed the neural embryonic phenotype of single and double-mutant mice for insulin-like growth factor-I (IGF-I) and leukemia inhibitory factor (LIF). The anatomical structure of the hippocampus, the cerebellum, and the olfactory epithelium, regions showing expression of both factors and their receptors, appeared largely normal in all mutant mice. In the fimbria and the spinal cord, similar patterns of glial fibrillary acidic protein (GFAP)-expressing astrocytes were found in wild-type and mutant mice. In contrast, single Igf-I and double-mutant mice showed a significant reduction in the number of trigeminal and facial motoneurons, whereas mice lacking LIF showed a significant reduction of trigeminal motoneurons. These results suggest that IGF-I and LIF regulate cooperatively motoneuron numbers in specific brain stem nuclei.Peer Reviewe