[show abstract][hide abstract] ABSTRACT: Medulloblastomas are brain tumors that arise in the cerebellum of children and contain stem cells in a perivascular niche thought to give rise to recurrence following radiation. We used several mouse models of medulloblastomas in parallel to better understand how the critical cell types in these tumors respond to therapy. In our models, the proliferating cells in the tumor bulk undergo radiation-induced, p53-dependent apoptotic cell death. Activation of Akt signaling via PTEN loss transforms these cells to a nonproliferating extensive nodularity morphology. By contrast, the nestin-expressing perivascular stem cells survive radiation, activate PI3K/Akt pathway, undergo p53-dependent cell cycle arrest, and re-enter the cell cycle at 72 h. Furthermore, the ability of these cells to induce p53 is dependent on the presence of PTEN. These cellular characteristics are similar to human medulloblastomas. Finally, inhibition of Akt signaling sensitizes cells in the perivascular region to radiation-induced apoptosis.
Genes & Development 03/2008; 22(4):436-48. · 12.44 Impact Factor
[show abstract][hide abstract] ABSTRACT: A connection between inflammation and carcinogenesis has long been known, but the precise mechanisms are just beginning to be understood. NF-kappaB proteins, transcription factors which integrate stress signals and orchestrate immune responses, have also recently been linked to carcinogenesis. Hallmarks of cancer development include self-sufficiency in growth signals, insensitivity to growth-inhibitors, evasion of apoptosis, limitless replicative potential, tissue invasion and metastasis, and sustained angiogenesis. NF-kappaB signaling has been implicated in each of these hallmarks, and recent experimental studies have illuminated the mechanistic pathways by which NF-kappaB signaling contributes to these aspects of carcinogenesis. This review will focus on recent experimental data supporting the hypothesis that inflammation promotes carcinogenesis, and that NF-kappaB signaling is at the heart of such inflammation.
Current Opinion in Genetics & Development 03/2008; 18(1):19-26. · 7.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Glioblastomas (GBMs) are highly lethal brain tumours with current therapies limited to palliation due to therapeutic resistance. We previously demonstrated that GBM stem cells (GSCs) display a preferential activation of DNA damage checkpoint and are relatively resistant to radiation. However, the molecular mechanisms underlying the preferential checkpoint response in GSCs remain undefined. Here, we show that L1CAM (CD171) regulates DNA damage checkpoint responses and radiosensitivity of GSCs through nuclear translocation of L1CAM intracellular domain (L1-ICD). Targeting L1CAM by RNA interference attenuated DNA damage checkpoint activation and repair, and sensitized GSCs to radiation. L1CAM regulates expression of NBS1, a critical component of the MRE11-RAD50-NBS1 (MRN) complex that activates ataxia telangiectasia mutated (ATM) kinase and early checkpoint response. Ectopic expression of NBS1 in GSCs rescued the decreased checkpoint activation and radioresistance caused by L1CAM knockdown, demonstrating that L1CAM signals through NBS1 to regulate DNA damage checkpoint responses. Mechanistically, nuclear translocation of L1-ICD mediates NBS1 upregulation via c-Myc. These data demonstrate that L1CAM augments DNA damage checkpoint activation and radioresistance of GSCs through L1-ICD-mediated NBS1 upregulation and the enhanced MRN-ATM-Chk2 signalling.
The EMBO Journal 02/2011; 30(5):800-13. · 9.82 Impact Factor
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