RESUMO
Cellular senescence triggers various types of heterochromatin remodeling that contribute to aging. However, the age-related mechanisms that lead to these epigenetic alterations remain elusive. Here, we asked how two key aging hallmarks, telomere shortening and constitutive heterochromatin loss, are mechanistically connected during senescence. We show that, at the onset of senescence, pericentromeric heterochromatin is specifically dismantled consisting of chromatin decondensation, accumulation of DNA breakages, illegitimate recombination and loss of DNA. This process is caused by telomere shortening or genotoxic stress by a sequence of events starting from TP53-dependent downregulation of the telomere protective protein TRF2. The resulting loss of TRF2 at pericentromeres triggers DNA breaks activating ATM, which in turn leads to heterochromatin decondensation by releasing KAP1 and Lamin B1, recombination and satellite DNA excision found in the cytosol associated with cGAS. This TP53-TRF2 axis activates the interferon response and the formation of chromosome rearrangements when the cells escape the senescent growth arrest. Overall, these results reveal the role of TP53 as pericentromeric disassembler and define the basic principles of how a TP53-dependent senescence inducer hierarchically leads to selective pericentromeric dismantling through the downregulation of TRF2.
Assuntos
Senescência Celular , Centrômero , Heterocromatina , Encurtamento do Telômero , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular , Cromatina , Dano ao DNA , Regulação para Baixo , Células HeLa , Humanos , Telômero/genética , Proteína 2 de Ligação a Repetições Teloméricas/metabolismoRESUMO
How mutations or dysfunction of CFTR may increase the risk of malignancies in various tissues remains an open question. Here we report the interaction between CFTR and an adherens junction molecule, AF-6/afadin, and its involvement in the development of colon cancer. We have found that CFTR and AF-6/afadin are co-localized at the cell-cell contacts and physically interact with each other in colon cancer cell lines. Knockdown of CFTR results in reduced epithelial tightness and enhanced malignancies, with increased degradation and reduced stability of AF-6/afadin protein. The enhanced invasive phenotype of CFTR-knockdown cells can be completely reversed by either AF-6/afadin over-expression or ERK inhibitor, indicating the involvement of AF-6/MAPK pathway. More interestingly, the expression levels of CFTR and AF-6/afadin are significantly downregulated in human colon cancer tissues and lower expression of CFTR and/or AF-6/afadin is correlated with poor prognosis of colon cancer patients. The present study has revealed a previously unrecognized interaction between CFTR and AF-6/afadin that is involved in the pathogenesis of colon cancer and indicated the potential of the two as novel markers of metastasis and prognostic predictors for human colon cancer.
Assuntos
Neoplasias do Colo/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Cinesinas/genética , Proteínas dos Microfilamentos/genética , Miosinas/genética , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulação para Baixo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Células HEK293 , Humanos , Cinesinas/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas dos Microfilamentos/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Miosinas/metabolismo , Invasividade Neoplásica , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Fenótipo , Prognóstico , Junções Íntimas/genética , Junções Íntimas/metabolismo , Junções Íntimas/patologiaRESUMO
Inflammatory Bowel Disease (IBD) is a complicated disease that arises as a consequence of the interaction among environment, genetic factors and autoimmunity. Available therapeutic interventions with pharmacological or biological drugs have a very selective action. Mesenchymal stem cells (MSCs) have been emerging as a promising cellular therapy for the treatment of IBD due to their multifaceted functions. This article summarizes recent progress in both preclinical studies and clinical trials employing MSCs in IBD treatment. We justify the use of MSC-based cell therapy as a novel strategy for IBD, discuss the biological roles that MSCs play underlying their therapeutic effects focusing on their immune-suppressive effects, illustrate methods to improve MSCs for better repair, and pinpoint the obstacles hindering their success and the challenges to overcome before their ultimate application.