RESUMEN
Senescent cells, formed in response to physiological and oncogenic stresses, facilitate protection from tumourigenesis and aid in tissue repair. However, accumulation of such cells in tissues contributes to age-related pathologies. Resistance of senescent cells to apoptotic stimuli may contribute to their accumulation, yet the molecular mechanisms allowing their prolonged viability are poorly characterized. Here we show that senescent cells upregulate the anti-apoptotic proteins BCL-W and BCL-XL. Joint inhibition of BCL-W and BCL-XL by siRNAs or the small-molecule ABT-737 specifically induces apoptosis in senescent cells. Notably, treatment of mice with ABT-737 efficiently eliminates senescent cells induced by DNA damage in the lungs as well as senescent cells formed in the epidermis by activation of p53 through transgenic p14(ARF). Elimination of senescent cells from the epidermis leads to an increase in hair-follicle stem cell proliferation. The finding that senescent cells can be eliminated pharmacologically paves the way to new strategies for the treatment of age-related pathologies.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/farmacología , Nitrofenoles/farmacología , Proteínas/antagonistas & inhibidores , Sulfonamidas/farmacología , Proteína bcl-X/antagonistas & inhibidores , Animales , Proteínas Reguladoras de la Apoptosis , Línea Celular , Proliferación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Daño del ADN , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Epidermis/patología , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Piperazinas/farmacología , Cultivo Primario de Células , Proteínas/genética , Proteínas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Proteína p14ARF Supresora de Tumor/genética , Proteína p14ARF Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMEN
Cellular senescence, a state of cell-cycle arrest accompanied by dramatic morphologic and metabolic changes, is a central means by which cells respond to physiologic stress and oncogene activity. Senescence is thought to play important roles in aging and in tumor suppression, yet the dynamics by which senescent cells are formed, their effects on tissue function and their eventual fate are poorly understood. To study cellular senescence within an adult tissue, we developed transgenic mice inducibly expressing p14(ARF) (human ortholog of murine p19(ARF)), a central activator of senescence. Induction of p14(ARF) in the epidermis rapidly led to widespread apoptosis and cell-cycle arrest, a stage that was transient, and was followed by p53-dependent cellular senescence. The endogenous Cdkn2a products p19(ARF) and p16(Ink4a) were activated by the transgenic p14(ARF) through p53, revealing a senescence-promoting feed-forward loop. Commitment of cells to senescence required continued p14(ARF) expression, indicating that entry into this state depends on a persistent signal. However, once formed, senescent cells were retained in the epidermis, often for weeks after transgene silencing, indicating an absence of an efficient rapidly acting mechanism for their removal. Stem cells in the hair follicle bulge were largely protected from apoptosis upon p14(ARF) induction, but irreversibly lost their ability to proliferate and initiate follicle growth. Interestingly, induction of epidermal hyperplasia prevented the appearance of senescent cells upon p14(ARF) induction. Our findings provide basic insights into the dynamics of cellular senescence, a central tumor- suppressive mechanism, and reveal the potential for prolonged retention of senescent cells within tissues.
