Notch Signaling in Human Neuroblastoma Cells
Neuroblastoma is a childhood tumor derived from the sympathetic nervous system (SNS). It is believed that the tumors arise from cells halted in their differentiation and due to their immature phenotype; they express proteins normally only detected during embryogenesis. One such protein is Hash-1, which is required for formation of the SNS. Hash-1 is a component of the Notch signaling cascade, which is involved in many cell fate decisions. In general, Notch activity maintains a pool of undifferentiated cells and dysregulated Notch signaling has been linked to development of several cancers. It has been shown that the Notch cascade is transiently induced during neuroblastoma cell differentiation in vitro and that persistent Notch expression inhibits this differentiation. These observations imply a role for Notch signaling in the blocked differentiation of neuroblastoma cells. In addition, neuroblastoma cells exposed to hypoxia, a common event of solid tumors, dedifferentiate. During this process, components of the Notch signaling cascade are up regulated. In this thesis we show that Hash-1 interacts with ubiquilin-1, a protein involved in protecting proteins from degradation. In addition, we show that valproic acid (VPA) induces differentiation of neuroblastoma cells by modulation of the Notch signaling cascade. Aberrant signaling through the EGF receptor is involved in the genesis of some human cancers. Several reports have shown cross talk between EGFR signaling and the Notch cascade. We show here that the Notch target Hes-1 can be directly regulated by Ras/MAPK signaling at both normoxia and hypoxia, without the activation of Notch receptors.
Source Type:Doctoral Dissertation
Keywords:MEDICINE; Hes-1; oncology; Medicin (människa och djur); Medicine (human and vertebrates); hypoxia; TGF-alpha; EGFR; ERK1/2; Ras/MAPK; differentiation; valproic acid; ubiquilin-1; neuroblastoma; Hash-1; Cytologi; onkologi; cancer; cancerology; Cytology; Notch
Date of Publication:01/01/2005