UC Berkeley

SnoN, a member of the Ski proto-oncoprotein family, was originally classified as an oncogene based on its ability to transform chicken and quail embryonic fibroblasts. Elevated levels of SnoN have been detected in many human carcinoma cell lines. Furthermore reduction of SnoN expression in breast and lung cancer cell lines impairs their ability to proliferate in culture and form tumors in vivo. Moreover, expression in mouse mammary glands of a SnoN fragment containing residues 1-366 promotes PyVmT-induced (polyomavirus middle T antigen) tumor growth and metastasis. These findings strongly support the idea that SnoN has pro-oncogenic properties. However, there is also evidence that SnoN might be anti-oncogenic as well. Although increased expression of SnoN has been observed in certain cancers and at specific stages of malignant transformation, downregulation of SnoN has been shown in other types of cancers. Loss of one allele of SnoN in mice has been shown to increase their susceptibility to chemical carcinogen-induced tumorigenesis. Overexpression of dSnoN (the Drosophila homologue of SnoN) has negative effects on cell growth. SnoN has also been reported to cooperate with p53 to regulate p53 target gene expression. Together, the evidence suggests that SnoN might play a dual role in tumorigenesis. How can SnoN possess two opposite functions in tumorigenesis? What are the mechanisms underlying the dual role of SnoN in tumorigenesis? And, what are the potential regulators of SnoN expression in different types and stages of cancer? My dissertation research aimed to answer those questions.

I have shown that elevated cellular SnoN expression has anti-oncogenic effects both in vivo and in culture. The levels of SnoN are tightly regulated in cells. SnoN expression is relatively low in normal cells, but is significantly elevated when cells are exposed to certain types of stress. Multiple pathways seem to function cooperatively to regulate the expression of SnoN in response to stress. I have shown that the ATM/ATR kinase, MEK/Erk kinase and PI3K kinase pathways, which are activated by stress signals, are necessary for upregulation of SnoN by stress (Chapter III). The elevated SnoN expression has anti-oncogenic functions by virtue of inducing premature senescence. SnoN-induced senescence is mediated by the interaction of SnoN with the PML-p53 pathway. SnoN interacts with PML and is recruited to PML nuclear bodies (Nbs), resulting in the stabilization and activation of p53 by competitively displacing Mdm2 from p53. In addition, SnoN enhances post-transcriptional modifications of p53 in PML NBs. Through these mechanisms, SnoN participates in activating the transcription of p53 target genes when recruited to their promoters together with p53. SnoN therefore mediates rapid p53 activation in response to specific cellular stress signals. In the absence of SnoN, p53-dependent stress responses are significantly delayed and early stage responses in stressed cells fail to be activated properly. Since p53 plays a central role in tumor suppression as well as regulation of ageing, activation of p53 by SnoN can prevent carcinogen-induced tumorigenesis and accelerate stress related ageing.