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1.
Proc Natl Acad Sci U S A ; 114(15): 3933-3938, 2017 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-28348210

RESUMEN

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in development and human disease, including cancer. It is currently thought that the four-point one, ezrin, radixin, moesin (FERM)-kinase domain linker, which contains autophosphorylation site tyrosine (Y) 397, is not required for in vivo FAK function until late midgestation. Here, we directly tested this hypothesis by generating mice with FAK Y397-to-phenylalanine (F) mutations in the germline. We found that Y397F embryos exhibited reduced mesodermal fibronectin (FN) and osteopontin expression and died during mesoderm development akin to FAK kinase-dead mice. We identified myosin-1E (MYO1E), an actin-dependent molecular motor, to interact directly with the FAK FERM-kinase linker and induce FAK kinase activity and Y397 phosphorylation. Active FAK in turn accumulated in the nucleus where it led to the expression of osteopontin and other FN-type matrix in both mouse embryonic fibroblasts and human melanoma. Our data support a model in which FAK Y397 autophosphorylation is required for FAK function in vivo and is positively regulated by MYO1E.


Asunto(s)
Quinasa 1 de Adhesión Focal/metabolismo , Melanoma/metabolismo , Miosinas/metabolismo , Neoplasias Cutáneas/metabolismo , Animales , Pérdida del Embrión/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Femenino , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Quinasa 1 de Adhesión Focal/química , Quinasa 1 de Adhesión Focal/genética , Humanos , Melanoma/patología , Mesodermo/embriología , Ratones Mutantes , Miosina Tipo I , Miosinas/química , Miosinas/genética , Osteopontina/genética , Osteopontina/metabolismo , Fosforilación , Embarazo , Dominios Proteicos , Neoplasias Cutáneas/patología , Tirosina/metabolismo
2.
Dose Response ; 19(1): 1559325821993665, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33716590

RESUMEN

The rapid advances in nuclear medicine have resulted in significant advantages for the field of oncology. The focus is on the application of radiopharmaceuticals as therapeuticals. In addition, the latest developments in cell biology (the understanding of the cell structure, function, metabolism, genetics, signaling, transformation) have given a strong scientific boost to radiation oncology. In this regard, the article discusses what is soon going to be a new jump in radiation oncology based on the already accumulated considerable knowledge at the cellular level about the mechanisms of cell transformation and tumor progression, cell response to radiation, cell resistance to apoptosis and radiation and cell radio-sensitivity. The mechanisms of resistance of tumor cells to radiation and the genetically determined individual sensitivity to radiation in patients (which creates the risk of radiation-induced acute and late side effects) are the 2 major challenges to overcome in modern nuclear medicine. The paper focuses on these problems and makes a detailed summary of the significance of the differences in the ionizing properties of radiopharmaceuticals and the principle of their application in radiation oncology that will shed additional light on how to make the anti-cancer radiotherapies more efficient and safe, giving some ideas for optimizations.

3.
J Cell Biochem ; 103(3): 857-64, 2008 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-17615554

RESUMEN

Rac1 is a Rho subfamily small GTPase which is highly expressed in epidermal keratinocytes. In mice the significance of Rac1 for the maintenance of the epidermis has been controversial. In keratinocytes from human origin, the role of Rac1 in the control of growth/differentiation is still obscure. In this study we used RNA interference to induce specific inhibition of Rac1 expression in cultured human keratinocytes and analyzed the consequences on proliferation and differentiation. We found that the autocrine proliferation of keratinocytes is unaltered by Rac1 silencing. However, the suppression of Rac1 induced premature differentiation as revealed by the expression of markers (keratin 10, involucrin), but the involved mechanism is independent of the activity of p38 mitogen-activated protein kinase. Rather, we found that the effects of Rac1 silencing on keratinocytes differentiation are concomitant with negative regulation of the Ser62/Thr58 phosphorylation on the transcription factor c-myc, a mechanism known to control post-translational stability of the c-myc protein. Thus, in growing human keratinocytes, Rac1 could impede the expression of premature differentiation markers, probably by exerting positive control on c-myc activity and its binding to specific promoters.


Asunto(s)
Proliferación Celular , Queratinocitos/citología , Queratinocitos/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Adulto , Animales , Diferenciación Celular , Células Cultivadas , Humanos , Queratinocitos/fisiología , Fosforilación , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Interferente Pequeño/genética , Piel/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas de Unión al GTP rho/metabolismo
4.
J Clin Oncol ; 33(23): 2509-15, 2015 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-26150443

RESUMEN

PURPOSE: Less than 20% of patients with melanoma who undergo sentinel lymph node (SLN) biopsy based on American Society of Clinical Oncology/Society of Surgical Oncology recommendations are SLN positive. We present a multi-institutional study to discover new molecular risk factors associated with SLN positivity in thin and intermediate-thickness melanoma. PATIENTS AND METHODS: Gene clusters with functional roles in melanoma metastasis were discovered by next-generation sequencing and validated by quantitative polymerase chain reaction using a discovery set of 73 benign nevi, 76 primary cutaneous melanoma, and 11 in-transit melanoma metastases. We then used polymerase chain reaction to quantify gene expression in a model development cohort of 360 consecutive thin and intermediate-thickness melanomas and a validation cohort of 146 melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. Logic and logistic regression analyses were used to develop a model for the likelihood of SLN metastasis from molecular, clinical, and histologic variables. RESULTS: ITGB3, LAMB1, PLAT, and TP53 expression were associated with SLN metastasis. The predictive ability of a model that included these molecular variables in combination with clinicopathologic variables (patient age, Breslow depth, and tumor ulceration) was significantly greater than a model that only considered clinicopathologic variables and also performed well in the validation cohort (area under the curve, 0.93; 95% CI, 0.87 to 0.97; false-positive and false-negative rates of 22% and 0%, respectively, using a 10% cutoff for predicted SLN metastasis risk). CONCLUSION: The addition of cell adhesion-linked gene expression variables to clinicopathologic variables improves the identification of patients with SLN metastases within 90 days of melanoma diagnosis.


Asunto(s)
Biomarcadores de Tumor/análisis , Adhesión Celular , Ganglios Linfáticos/patología , Melanoma/patología , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/patología , Adulto , Anciano , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Integrina beta3/análisis , Laminina/análisis , Modelos Logísticos , Metástasis Linfática , Masculino , Melanoma/química , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de Riesgo , Neoplasias Cutáneas/química , Activador de Tejido Plasminógeno/análisis , Proteína p53 Supresora de Tumor/análisis
5.
Biochem Biophys Res Commun ; 359(3): 834-9, 2007 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-17568564

RESUMEN

Proliferation of dermal fibroblasts is crucial for the maintenance of skin. The small Rho GTPase, Rac1, has been identified as a key transducer of proliferative signals in various cell types, but in normal human dermal fibroblasts its significance to cell growth control has not been studied. In this study, we applied the method of RNA interference to suppress endogenous Rac1 expression and examined the consequences on human skin fibroblasts. Rac1 knock-down resulted in inhibition of DNA synthesis. This effect was not mediated by inhibition of the central transducer of proliferative stimuli, ERK1/2 or by activation of the pro-apoptotic p38. Rather, as a consequence of the suppressed Rac1 expression we observed a significant decrease in phosphorylation of c-myc, revealing for the first time that in human fibroblasts Rac1 exerts control on proliferation through c-myc phosphorylation. Thus Rac1 activates proliferation of normal fibroblasts through stimulation of c-myc phosphorylation without affecting ERK1/2 activity.


Asunto(s)
Proteínas Proto-Oncogénicas c-myc/metabolismo , Piel/citología , Piel/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Proliferación Celular , Células Cultivadas , Fibroblastos , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación , ARN Interferente Pequeño/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteína de Unión al GTP rac1/genética
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