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Zool Res ; 42(5): 650-659, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34472226


Phosphatidylserine (PS) is distributed asymmetrically in the plasma membrane of eukaryotic cells. Phosphatidylserine flippase (P4-ATPase) transports PS from the outer leaflet of the lipid bilayer to the inner leaflet of the membrane to maintain PS asymmetry. The ß subunit TMEM30A is indispensable for transport and proper function of P4-ATPase. Previous studies have shown that the ATP11A and TMEM30A complex is the molecular switch for myotube formation. However, the role of Tmem30a in skeletal muscle regeneration remains elusive. In the current study, Tmem30a was highly expressed in the tibialis anterior (TA) muscles of dystrophin-null ( mdx) mice and BaCl 2-induced muscle injury model mice. We generated a satellite cell (SC)-specific Tmem30a conditional knockout (cKO) mouse model to investigate the role of Tmem30a in skeletal muscle regeneration. The regenerative ability of cKO mice was evaluated by analyzing the number and diameter of regenerated SCs after the TA muscles were injured by BaCl 2-injection. Compared to the control mice, the cKO mice showed decreased Pax7 + and MYH3 + SCs, indicating diminished SC proliferation, and decreased expression of muscular regulatory factors (MYOD and MYOG), suggesting impaired myoblast proliferation in skeletal muscle regeneration. Taken together, these results demonstrate the essential role of Tmem30a in skeletal muscle regeneration.

Proteínas de Membrana/metabolismo , Músculo Esquelético/fisiologia , Regeneração/fisiologia , Células Satélites de Músculo Esquelético/metabolismo , Animais , Proliferação de Células , Distrofina/genética , Distrofina/metabolismo , Antagonistas de Estrogênios/toxicidade , Regulação da Expressão Gênica/fisiologia , Genótipo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos mdx , Camundongos Knockout , Músculo Esquelético/efeitos dos fármacos , Proteína MyoD/genética , Proteína MyoD/metabolismo , Miogenina/genética , Miogenina/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Fator de Transcrição PAX7/genética , Fator de Transcrição PAX7/metabolismo , Regeneração/genética , Tamoxifeno/toxicidade
J Surg Oncol ; 94(5): 396-402, 2006 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16967437


BACKGROUND AND OBJECTIVES: Goblet cell carcinoid, a rare tumor of intermediate malignant potential, is known to account for a significant minority of appendiceal neoplasms. Sixteen new cases of gastrointestinal goblet cell carcinoid were reviewed to describe their presentation, treatment, and outcome. METHODS: A review of 16 cases from a single institution. RESULTS: Sixteen patients were diagnosed with goblet cell carcinoid between 1995 and 2005. Presenting diagnoses included appendicitis (n=8), abdominal or liver mass (n=5), uterine fibroids (n=1), ovarian mass (n=1), and Crohn's Disease exacerbation (n=1). Mean follow-up was 12 months with a mortality of 19% (n=3). Patients were divided into two groups: those where the diagnosis was an incidental finding at operation (Group 1) and those where the presentation was of an abdominal mass or metastatic disease (Group 2). Nine of ten patients in Group 1 initially received appendectomies. Group 2 included patients presenting with Krukenberg type lesions (n=2) and abdominal masses (n=4). CONCLUSIONS: Goblet cell carcinoid is a rare malignant tumor largely affecting the appendix. In patients presenting with appendicitis, our series does not support the recommendation of right hemicolectomy based on pathologic diagnosis alone and surgical intervention must be customized to the individual patient.

Neoplasias do Apêndice/terapia , Tumor Carcinoide/terapia , Neoplasias Gastrointestinais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apendicectomia , Neoplasias do Apêndice/diagnóstico , Neoplasias do Apêndice/cirurgia , Apendicite/complicações , Apendicite/cirurgia , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/cirurgia , Colectomia , Feminino , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/cirurgia , Humanos , Achados Incidentais , Neoplasias Hepáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Estudos Retrospectivos , Neoplasias Uterinas/diagnóstico
J Biol Chem ; 279(33): 34898-902, 2004 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-15184376


UV light induces a delayed and prolonged (3-20 h) activation of NFkappaB when compared with the immediate and acute (10-90 min) activation of NFkappaB in response to tumor necrosis factor alpha treatment. In the early phase (3-12 h) of NFkappaB activation, UV light reduces inhibitor of NFkappaB (IkappaB) through an IkappaB kinase-independent, but polyubiquitin-dependent, pathway. However, the mechanism for the UV light-induced reduction of IkappaB and activation of NFkappaB is not known. In this report, we show that UV light down-regulates the total amount of IkappaB through decreasing IkappaB mRNA translation. Our data show that UV light inhibits translation of IkappaB in wild-type mouse embryo fibroblasts (MEF(S/S)) and that this inhibition is prevented in MEF(A/A) cells in which the phosphorylation site, Ser-51 in the eukaryotic translation initiation factor 2 alpha-subunit, is replaced with a non-phosphorylatable Ala (S51A). Our data also show that UV light-induced NFkappaB activation is delayed in MEF(A/A) cells and in an MCF-7 cell line that is stably transfected with a trans-dominant negative mutant protein kinase-like endoplasmic reticulum kinase (PERK). These results suggest that UV light-induced eukaryotic translation initiation factor 2 alpha-subunit phosphorylation translationally inhibits new IkappaB synthesis. Without a continuous supply of newly synthesized IkappaB, the existing IkappaB is degraded through a polyubiquitin-dependent proteasomal pathway leading to NFkappaB activation. Based upon our results, we propose a novel mechanism by which UV light regulates early phase NFkappaB activation by means of an ER-stress-induced translational inhibition pathway.

Proteínas I-kappa B/metabolismo , NF-kappa B/metabolismo , Biossíntese de Proteínas , Raios Ultravioleta , Animais , Linhagem Celular Tumoral , Regulação para Baixo , Fator de Iniciação 2 em Eucariotos/metabolismo , Fibroblastos/metabolismo , Genes Dominantes , Humanos , Luz , Camundongos , Microscopia de Fluorescência , Modelos Biológicos , Inibidor de NF-kappaB alfa , Fosforilação , RNA Mensageiro/metabolismo , Serina/química , Fatores de Tempo , eIF-2 Quinase/metabolismo
J Biol Chem ; 277(20): 18077-83, 2002 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-11877419


Exposure to ultraviolet light can cause inflammation, premature skin aging, and cancer. UV irradiation alters the expression of multiple genes that encode functions to repair DNA damage, arrest cell growth, and induce apoptosis. In addition, UV irradiation inhibits protein synthesis, although the mechanism is not known. In this report, we show that UV irradiation induces phosphorylation of eukaryotic translation initiation factor 2 on the alpha-subunit (eIF2alpha) and inhibits protein synthesis in a dosage- and time-dependent manner. The UV-induced phosphorylation of eIF2alpha was prevented by the overexpression of a non-phosphorylatable mutant of eIF2alpha (S51A). PERK is an eIF2alpha protein kinase localized to the endoplasmic reticulum that is activated by the accumulation of unfolded proteins in the endoplasmic reticulum. Expression of trans-dominant-negative mutants of PERK also prevented eIF2alpha phosphorylation upon UV treatment and protected from the associated translation attenuation. The luminal domain of dominant-negative mutant PERK formed heterodimers with endogenous PERK to inhibit the PERK signaling pathway. In contrast, eIF2alpha phosphorylation was not inhibited by overexpression of a trans-dominant-negative mutant kinase, PKR, supporting the theory that UV-induced eIF2alpha phosphorylation is specifically mediated by PERK. These results support a novel mechanism by which UV irradiation regulates translation via an endoplasmic reticulum-stress signaling pathway.

Retículo Endoplasmático/efeitos da radiação , Biossíntese de Proteínas/efeitos da radiação , Raios Ultravioleta/efeitos adversos , eIF-2 Quinase/efeitos da radiação , Animais , Células COS , Cricetinae , Dimerização , Relação Dose-Resposta à Radiação , Eletroforese em Gel de Poliacrilamida , Retículo Endoplasmático/enzimologia , Ativação Enzimática/efeitos da radiação , Fator de Iniciação 2 em Eucariotos/metabolismo , Fosforilação , Fatores de Tempo , Células Tumorais Cultivadas , eIF-2 Quinase/metabolismo