Notch1 and Notch2 Have Opposite Effects on Embryonal Brain Tumor Growth

Abstract

The role of Notch signaling in tumorigenesis can vary; Notch1 acts as an oncogene in some neoplasms, and a tumor suppressor in others. Here, we show that different Notch receptors can have opposite effects in a single tumor type. Expression of truncated, constitutively active Notch1 or Notch2 in embryonal brain tumor cell lines caused antagonistic effects on tumor growth. Cell proliferation, soft agar colony formation, and xenograft growth were all promoted by Notch2 and inhibited by Notch1. We also found that Notch2 receptor transcripts are highly expressed in progenitor cell-derived brain tumors such as medulloblastomas, whereas Notch1 is scarce or undetectable. This parallels normal cerebellar development, during which Notch2 is predominantly expressed in proliferating progenitors and Notch1 in postmitotic differentiating cells. Given the oncogenic effects of Notch2, we analyzed its gene dosage in 40 embryonal brain tumors, detecting an increased copy number in 15% of cases. Notch2 gene amplification was confirmed by fluorescence in situ hybridization in one case with extremely high Notch2 mRNA levels. In addition, expression of the Notch pathway target gene Hes1 in medulloblastomas was associated with significantly shorter patient survival (P ‫؍‬ 0.01). Finally, pharmacological inhibition of Notch signaling suppresses growth of medulloblastoma cells. Our data indicate that Notch1 and Notch2 can have opposite effects on the growth of a single tumor type, and show that Notch2 can be overexpressed after gene amplification in human tumors.

A ubiquitin ligase, skeletrophin, is a negative regulator of melanoma invasion

“…Very recently, Balint et al (2005) also demonstrated that activation of Notch1 pathway could promote melanoma progression. These data suggested that activation of both Notch1 and 2 receptors could be oncogenic in melanoma cells; however, it should also be noted that Notch1 and 2 can play an opposite role in tumorigenesis in a single tumor cell type (Fan et al, 2004;Parr et al, 2004). In the present study, we could not find any significant differences in the expression of the Notch receptor and ligand between the skeletrophin-positive and -negative melanoma cells tested.…”

DLK1: increased expression in gliomas and associated with oncogenic activities

“…The oncogenic potential of Notch-1 has been shown in T-cell leukemia in which the truncated form of Notch-1 is expressed (Ellisen et al, 1991). On the other hand, Notch1 can cause growth arrest in medulloblastomas, mammalian skin tumors, and small-cell lung cancers (Sriuranpong et al, 2001;Nicolas et al, 2003;Fan et al, 2004). DLK1 is a negative regulator of Notch1 activation and decreases expression of Hes-1 (a downstream target of Notch-1) in 3T3-L1 fibroblasts (Baladron et al, 2005).…”

Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-β signaling

“…The transcriptional activities of Notch1ICD, Notch2-ICD and Notch3ICD were markedly different from each other, and the activities of Notch1ICD or Notch3ICD were reduced by coexpression of Notch2ICD. Fan et al (2004) also showed that Notch1ICD and Notch2ICD can have opposite effects on the growth of a single tumor type. Moreover, Notch1 acts as an oncogene in some carcinomas (Capobianco et al, 1997;Weijzen et al, 2002;Kiaris et al, 2004), and as a tumor suppressor (Nicolas et al, 2003;Fan et al, 2004) in others.…”