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PDF file - 65K, Supplementary Figure 6. A schematic drawing of full length N1ICD in mouse, N1ICD allele analyzed in this study, and the ACTB-Notch1 allele previously published (Yang et al., 2004) and analyzed in Supplementary Figure 6.

PDF file - 133K, Supplementary Figure 3. Reduced p53 dose rescues precocious GFAP expression in the N1ICD;hGFAP-cre brains.

PDF file - 84K, Supplementary Figure 2. Reduced p53 dose rescues brain sizes in N1ICD;hGFAP-cre transgenic mice.

While activation of the Notch pathway is observed in many human cancers, it is unknown whether elevated Notch1 expression is sufficient to initiate tumorigenesis in most tissues. To test the oncogenic potential of Notch1 in solid tumors, we expressed an activated form of Notch1 (N1ICD) in the developing mouse brain. N1ICD;hGFAP-cre mice were viable but developed severe ataxia and seizures, and died by weaning age. Analysis of transgenic embryo brains revealed that N1ICD expression induced p53-dependent apoptosis. When apoptosis was blocked by genetic deletion of p53, 30% to 40% of N1ICD;GFAP-cre;p53+/− and N1ICD;GFAP-cre;p53−/− mice developed spontaneous medulloblastomas. Interestingly, N1ICD-induced medulloblastomas most closely resembled the sonic hedgehog subgroup of human medulloblastoma at the molecular level. Surprisingly, N1ICD-induced tumors do not maintain high levels of the Notch pathway gene expression, except for Notch2, showing that initiating oncogenic events may not be decipherable by analyzing growing tumors in some cases. In summary, this study shows that Notch1 has an oncogenic potential in the brain when combined with other oncogenic hits, such as p53 loss, and provides a novel mouse model of medulloblastoma. Cancer Res; 73(17); 5381–90. ©2013 AACR.

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PDF file - 158K, Supplementary Figure 1. Reduced p53 dose rescues apoptosis in N1ICD;hGFAP-cre brains.

PDF file - 199K, Supplementary Figure 5. Increased apoptosis and reduced proliferation of neural precursor cells in ACTB-N1ICD brains.

PDF file - 84K, Supplementary Figure 4. N1ICD induced medulloblastomas.

La Jolla, CA. Protein synthesis is vital for cell function and disturbances in translation are associated with cancer, neurological disorders and other diseases. Although regulation of translation is thought to largely occur at initiation, elongation, the reiterative addition of amino acids by the ribosome, is emerging as a translational phase that is also highly regulated. Transfer RNAs, the adaptor molecules essential for elongation are encoded by several hundreds of nuclear genes in higher eukaryotes suggesting great functional redundancy. Our work has defined epistatic interactions between mutations in a mammalian tRNA gene and a novel ribosome rescue factor, defining the importance of individual tRNA genes in translation and the pathologies that can arise from disruptions in this process. Citation Format: Susan L. Ackerman. Ribosome stalling and disease. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA13.