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1.
Int J Mol Sci ; 24(17)2023 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-37685856

RESUMEN

Muscular dystrophy is a heterogenous group of hereditary muscle disorders caused by mutations in the genes responsible for muscle development, and is generally defined by a disastrous progression of muscle wasting and massive loss in muscle regeneration. Pax7 is closely associated with myogenesis, which is governed by various signaling pathways throughout a lifetime and is frequently used as an indicator in muscle research. In this review, an extensive literature search adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed to identify research that examined signaling pathways in living models, while quantifying Pax7 expression in myogenesis. A total of 247 articles were retrieved from the Web of Science (WoS), PubMed and Scopus databases and were thoroughly examined and evaluated, resulting in 19 articles which met the inclusion criteria. Admittedly, we were only able to discuss the quantification of Pax7 carried out in research affecting various type of genes and signaling pathways, rather than the expression of Pax7 itself, due to the massive differences in approach, factor molecules and signaling pathways analyzed across the research. However, we highlighted the thorough evidence for the alteration of the muscle stem cell precursor Pax7 in multiple signaling pathways described in different living models, with an emphasis on the novel approach that could be taken in manipulating Pax7 expression itself in dystrophic muscle, towards the discovery of an effective treatment for muscular dystrophy. Therefore, we believe that this could be applied to the potential gap in muscle research that could be filled by tuning the well-established marker expression to improve dystrophic muscle.


Asunto(s)
Distrofias Musculares , Humanos , Distrofias Musculares/genética , Músculos , Bases de Datos Factuales , Desarrollo de Músculos , Transducción de Señal , Factor de Transcripción PAX7/genética
2.
Commun Biol ; 5(1): 1071, 2022 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-36207400

RESUMEN

Whether a small GTPase RhoA plays a role in the pathology of abdominal aortic aneurysm (AAA) has not been determined. We show here that RhoA expression is reduced in human AAA lesions, compared with normal areas. Furthermore, incidence of AAA formation is increased in vascular smooth muscle cell (VSMC)-specific RhoA conditional knockout (cKO) mice. The contractility of the aortic rings and VSMCs from RhoA cKO mice is reduced, and expression of genes related to the VSMC contractility is attenuated by loss of RhoA. RhoA depletion activates the mitogen-activated protein (MAP) kinase signaling, including MAP4K4, in the aorta and VSMCs. Inhibition of MAP4K4 activity by DMX-5804 decreases AAA formation. Set, a binding protein to active RhoA, functions as an activator of MAP4K4 by sequestering PP2A, an inhibitor of MAP4K4, in the absence of RhoA. In conclusion, RhoA counteracts AAA formation through inhibition of MAP4K4 in cooperation with Set.


Asunto(s)
Aneurisma de la Aorta Abdominal , Músculo Liso Vascular , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Animales , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/prevención & control , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Mitógenos , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteína de Unión al GTP rhoA/genética , Quinasa de Factor Nuclear kappa B
3.
Cancer Sci ; 112(10): 4005-4012, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34420253

RESUMEN

Tumor growth and progression are complex processes mediated by mutual interactions between cancer cells and their surrounding stroma that include diverse cell types and acellular components, which form the tumor microenvironment. In this environment, direct intercellular communications play important roles in the regulation of the biological behaviors of tumors. However, the underlying molecular mechanisms are insufficiently defined. We used an in vitro coculture system to identify genes that were specifically expressed at higher levels in cancer cells associated with stromal cells. Major examples included epithelial membrane protein 1 (EMP1) and stomatin, which positively and negatively regulate tumor progression, respectively. EMP1 promotes tumor cell migration and metastasis via activation of the small GTPase Rac1, while stomatin strongly suppresses cell proliferation and induces apoptosis of cancer cells via inhibition of Akt signaling. Here we highlight important aspects of EMP1, stomatin, and their family members in cancer biology. Furthermore, we consider the molecules that participate in intercellular communications and signaling transduction between cancer cells and stromal cells, which may affect the phenotypes of cancer cells in the tumor microenvironment.


Asunto(s)
Comunicación Celular/fisiología , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Superficie Celular/metabolismo , Células del Estroma/fisiología , Microambiente Tumoral/fisiología , Apoptosis/fisiología , Cadherinas/metabolismo , Movimiento Celular/fisiología , Proliferación Celular , Técnicas de Cocultivo , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Proteínas de la Membrana/genética , Invasividad Neoplásica , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Superficie Celular/genética , Proteína de Unión al GTP rac1/metabolismo
4.
J Biol Chem ; 296: 100761, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33971198

RESUMEN

Diabetes mellitus (DM) causes injury to tissues and organs, including to the heart and kidney, resulting in increased morbidity and mortality. Thus, novel potential therapeutics are continuously required to minimize DM-related organ damage. We have previously shown that dipeptidyl peptidase III (DPPIII) has beneficial roles in a hypertensive mouse model, but it is unknown whether DPPIII has any effects on DM. In this study, we found that intravenous administration of recombinant DPPIII in diabetic db/db mice for 8 weeks suppressed the DM-induced cardiac diastolic dysfunctions and renal injury without alteration of the blood glucose level. This treatment inhibited inflammatory cell infiltration and fibrosis in the heart and blocked the increase in albuminuria by attenuating the disruption of the glomerular microvasculature and inhibiting the effacement of podocyte foot processes in the kidney. The beneficial role of DPPIII was, at least in part, mediated by the cleavage of a cytotoxic peptide, named Peptide 2, which was increased in db/db mice compared with normal mice. This peptide consisted of nine amino acids, was a digested fragment of complement component 3 (C3), and had an anaphylatoxin-like effect determined by the Miles assay and chemoattractant analysis. The effect was dependent on its interaction with the C3a receptor and protein kinase C-mediated RhoA activation downstream of the receptor in endothelial cells. In conclusion, DPPIII plays a protective role in the heart and kidney in a DM animal model through cleavage of a peptide that is a part of C3.


Asunto(s)
Cardiomiopatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/uso terapéutico , Corazón/efectos de los fármacos , Riñón/efectos de los fármacos , Sustancias Protectoras/uso terapéutico , Animales , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/fisiopatología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/fisiopatología , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Terapia Enzimática , Corazón/fisiopatología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Ratones Endogámicos C57BL , Sustancias Protectoras/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapéutico
5.
Cancer Res ; 81(9): 2318-2331, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33757977

RESUMEN

The growth and progression of cancers are crucially regulated by the tumor microenvironment where tumor cells and stromal cells are mutually associated. In this study, we found that stomatin expression was markedly upregulated by the interaction between prostate cancer cells and stromal cells. Stomatin suppressed cancer cell proliferation and enhanced apoptosis in vitro and inhibited xenograft tumor growth in vivo. Stomatin inhibited Akt activation, which is mediated by phosphoinositide-dependent protein kinase 1 (PDPK1). PDPK1 protein stability was maintained by its binding to HSP90. Stomatin interacted with PDPK1 and interfered with the PDPK1-HSP90 complex formation, resulting in decreased PDPK1 expression. Knockdown of stomatin in cancer cells elevated Akt activation and promoted cell increase by promoting the interaction between PDPK1 and HSP90. Clinically, stomatin expression levels were significantly decreased in human prostate cancer samples with high Gleason scores, and lower expression of stomatin was associated with higher recurrence of prostate cancer after the operation. Collectively, these findings demonstrate the tumor-suppressive effect of stromal-induced stomatin on cancer cells. SIGNIFICANCE: These findings reveal that interactions with stromal cells induce expression of stomatin in prostate cancer cells, which suppresses tumor growth via attenuation of the Akt signaling axis.


Asunto(s)
Proliferación Celular/genética , Proteínas de la Membrana/metabolismo , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genética , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/metabolismo , Anciano , Animales , Apoptosis/genética , Comunicación Celular , Técnicas de Silenciamiento del Gen , Células HEK293 , Células Hep G2 , Humanos , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neoplasias de la Próstata/patología , Células del Estroma/metabolismo , Transfección , Carga Tumoral/genética , Ensayos Antitumor por Modelo de Xenoinjerto
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