RESUMO
Notch signaling is frequently hyperactivated in breast cancer, but how the enhanced signaling contributes to the tumor process is less well understood. In this report, we identify the proinflammatory cytokine interleukin-6 (IL-6) as a novel Notch target in breast tumor cells. Enhanced Notch signaling upregulated IL-6 expression, leading to activation of autocrine and paracrine Janus kinase/signal transducers and activators of transcription signaling. IL-6 upregulation was mediated by non-canonical Notch signaling, as it could be effectuated by a cytoplasmically localized Notch intracellular domain and was independent of the DNA-binding protein CSL. Instead, Notch-mediated IL-6 upregulation was controlled by two proteins in the nuclear factor (NF)-κB signaling cascade, IKKα and IKKß (inhibitor of nuclear factor kappa-B kinase subunit alpha and beta, respectively), as well as by p53. Activation of IL-6 by Notch required IKKα/IKKß function, but interestingly, did not engage canonical NF-κB signaling, in contrast to IL-6 activation by inflammatory agents such as lipopolysaccharide. With regard to p53 status, IL-6 expression was upregulated by Notch when p53 was mutated or lost, and restoring wild-type p53 into p53-mutated or -deficient cells abrogated the IL-6 upregulation. Furthermore, Notch-induced transcriptomes from p53 wild-type and -mutated breast tumor cell lines differed extensively, and for a subset of genes upregulated by Notch in a p53-mutant cell line, this upregulation was reduced by wild-type p53. In conclusion, we identify IL-6 as a novel non-canonical Notch target gene, and reveal roles for p53 and IKKα/IKKß in non-canonical Notch signaling in breast cancer and in the generation of cell context-dependent diversity in the Notch signaling output.
Assuntos
Neoplasias da Mama/patologia , Quinase I-kappa B/metabolismo , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Receptores Notch/metabolismo , Fatores de Transcrição STAT/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Comunicação Autócrina , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-6/genética , Macrófagos/patologia , Comunicação Parácrina , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Transcriptoma , Regulação para CimaRESUMO
The rapidly evolving field of regenerative medicine holds much promise for cell-based therapies for a range of debilitating conditions from spinal cord injury to haematological and neurological diseases. The groundbreaking discovery of induced pluripotent stem (iPS) cells has offered new perspectives on disease progression and the possibility of patient-specific cell transplants. In this review we first give a brief history of the field of regenerative medicine and then discuss the current state of regenerative medicine with a focus on embryonic stem cells and iPS cells. In order to keep abreast with this rapidly developing field, the Journal of Internal Medicine organized a 2-day Symposium, on March 12-13(th) 2009, at the Karolinska Insitute in Stockholm, which featured talks by 19 leading scientists in the field of regenerative medicine. In this review, we discuss the Symposium and introduce six accompanying review articles, by Symposium speakers, which focus on some of the topics discussed at the meeting.
Assuntos
Pesquisa Biomédica/tendências , Epigênese Genética , Células-Tronco Pluripotentes/fisiologia , Medicina Regenerativa/tendências , Engenharia Tecidual , Animais , Diferenciação Celular/fisiologia , Humanos , Camundongos , Transplante de Células-Tronco , SuéciaRESUMO
Mammalian central nervous system (CNS) development is a highly organized process involving the precise and coordinated timing of cell-cycle exit, differentiation, survival, and migration. These events require proper expression of pro-neuronal genes but also repression of alternative cell fates and restriction of cell-type-specific gene expression. Here, we show that the cyclin-dependent kinase (CDK) inhibitor p57Kip2 interacted with pro-neuronal basic helix-loop-helix (bHLH) factors such as Mash1, NeuroD, and Nex/Math2. Increased levels of p57Kip2 inhibited Mash1 transcriptional activity independently of CDK interactions and acted as a direct repressor in transcriptional assays. Proliferating telencephalic neural progenitors co-expressed basal levels of Mash1 and p57Kip2, and endogenous p57Kip2 accumulated transiently in the nuclei of neural stem cells (NSCs) during early stages of astrocyte differentiation mediated by ciliary neurotrophic factor (CNTF), independent of cell-cycle exit and at times when Mash1 expression was still prominent. In accordance with these observations, gain- and loss-of-function studies showed that p57Kip2 repressed neuronal differentiation after mitogen withdrawal, but exerted little or no effect on CNTF-mediated astroglial differentiation of NSCs. Our data suggest a novel role for p57Kip2 as a context-dependent repressor of neurogenic transcription factors and telencephalic neuronal differentiation.