RESUMEN
Osteoclast-mediated excessive bone resorption was highly related to diverse bone diseases including osteoporosis. BRISC and BRCA1-A complex member 2 (Babam2) was an evolutionarily conserved protein that is highly expressed in bone tissues. However, whether Babam2 is involved in osteoclast formation is still unclear. In this study, we identify Babam2 as an essential negative regulator of osteoclast formation. We demonstrate that Babam2 knockdown significantly accelerated osteoclast formation and activity, while Babam2 overexpression blocked osteoclast formation and activity. Moreover, we demonstrate that the bone resorption activity was significantly downregulated in Babam2-transgenic mice as compared with wild-type littermates. Consistently, the bone mass of the Babam2-transgenic mice was increased. Furthermore, we found that Babam2-transgenic mice were protected from LPS-induced bone resorption activation and thus reduced the calvarial bone lesions. Mechanistically, we demonstrate that the inhibitory effects of Babam2 on osteoclast differentiation were dependent on Hey1. As silencing Hey1 largely diminished the effects of Babam2 on osteoclastogenesis. Finally, we show that Babam2 interacts with Hey1 to inhibit Nfatc1 transcription. In sum, our results suggested that Babam2 negatively regulates osteoclastogenesis and bone resorption by interacting with Hey1 to inhibit Nfatc1 transcription. Therefore, targeting Babam2 may be a novel therapeutic approach for osteoclast-related bone diseases.
Asunto(s)
Resorción Ósea , Proteínas de Ciclo Celular , Factores de Transcripción NFATC , Proteínas del Tejido Nervioso , Proteínas Nucleares , Osteogénesis , Animales , Resorción Ósea/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciación Celular/genética , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Osteoclastos/metabolismo , Osteogénesis/genética , Ligando RANK/metabolismoRESUMEN
Resistance to radiotherapy is frequently observed in the clinic and leads to poor prognosis of non-small cell lung cancer (NSCLC). How to overcome resistance to radiotherapy is a challenge in the treatment of NSCLC. In this study, PPDPF was found to be upregulated in NSCLC tissues and cell lines, and its expression negatively correlated with the overall survival of patients with NSCLC. PPDPF promoted the growth, colony formation and invasion of lung cancer cells. Moreover, knockout of PPDPF inhibited tumorigenesis in the KL (KrasG12D; LKB1f/f) mouse model of lung cancer. Additionally, overexpression of PPDPF led to radioresistance in lung cancer cells, and knockdown of PPDPF sensitized lung cancer cells to radiotherapy. Mechanistically, PPDPF interacted with BABAM2 (an antiapoptotic protein) and blocked its ubiquitination by MDM2, thus stabilizing BABAM2 and promoting the radioresistance of lung cancer cells. Our present study suggested PPDPF as a therapeutic target in NSCLC.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/radioterapia , Animales , Carcinogénesis , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación hacia Abajo , Humanos , Ratones , Ratones Desnudos , Pronóstico , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BRISC and BRCA1-A complex member 2 (Babam2) plays an essential role in promoting cell cycle progression and preventing cellular senescence. Babam2-deficient fibroblasts show proliferation defect and premature senescence compared with their wild-type (WT) counterpart. Pluripotent mouse embryonic stem cells (mESCs) are known to have unlimited cell proliferation and self-renewal capability without entering cellular senescence. Therefore, studying the role of Babam2 in ESCs would enable us to understand the mechanism of Babam2 in cellular aging, cell cycle regulation, and pluripotency in ESCs. For this study, we generated Babam2 knockout (Babam2-/-) mESCs to investigate the function of Babam2 in mESCs. We demonstrated that the loss of Babam2 in mESCs leads to abnormal G1 phase retention in response to DNA damage induced by gamma irradiation or doxorubicin treatments. Key cell cycle regulators, CDC25A and CDK2, were found to be degraded in Babam2-/- mESCs following gamma irradiation. In addition, Babam2-/- mESCs expressed p53 strongly and significantly longer than in control mESCs, where p53 inhibited Nanog expression and G1/S cell cycle progression. The combined effects significantly reduced developmental pluripotency in Babam2-/- mESCs. In summary, Babam2 maintains cell cycle regulation and pluripotency in mESCs in response to induced DNA damage.