Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2

Abstract

The hedgehog (Hh) signaling pathway regulates the development of many organs in mammals, and activation of this pathway is widely observed in human cancers. Although it is known that Hh signaling activates the expression of genes involved in cell growth, the precise role of the Hh pathway in cancer development is still unclear. Here, we show that constitutively activated mutants of oncogenesis ͉ ubiquitination ͉ cell growth ͉ apoptosis

p53 stabilization induces apoptosis in chronic myeloid leukemia blast crisis cells

“…65 The Wnt transcriptional regulators b-catenin and TCF4 are negatively regulated by p53 through degradation 66 and direct negative transcriptional regulation, 67 respectively. In addition, the increased HDM2 protein level caused by Hedgehog 68 and BCR-ABL 12 signaling can be counteracted by MI-219. 35 Therefore, p53 control of multiple CML pathways may be appropriate for therapeutic intervention.…”

Protecting the hedgerow: p53 and Hedgehog pathway interactions

“…65 Taken together with in vivo data showing a restriction of Gli1-driven tumorigenesis and proliferation only in the presence of p53, a GLI1-p53 inhibitory loop regulating neural stem cell and tumor cell numbers was proposed. While Gli1 has previously been shown to repress p53 through the activation of MDM2, 66 this study uncovers a feedback mechanism in which p53 can in turn inhibit the activity, nuclear localization and levels of Gli1.…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Indeed, almost all Ptch1 þ /À mice in p53 null background develop medulloblastomas, BCCs and other tumor types whereas Ptch1 þ /À mice in p53 wildtype background have a low frequency of tumor development (Romer et al, 2004;Epstein, 2008). Recent studies reveal that Hh signaling overrides p53-mediated signaling through regulation of MDM2, and p53 negatively regulates Gli1 expression (Abe et al, 2008;Stecca and Ruiz i Altaba, 2009). This feedback regulatory loop seems to be required for maintaining stem cell number and cancer cell number.…”