Huntzicker, E. G. et al. Dual degradation signals control Gli protein stability and tumor formation. Genes Dev. 20, 276-281

Program in Epithelial Biology, Stanford University, Stanford, California 94305, USA.
Genes & Development (Impact Factor: 10.8). 03/2006; 20(3):276-81. DOI: 10.1101/gad.1380906
Source: PubMed


Regulated protein destruction controls many key cellular processes with aberrant regulation increasingly found during carcinogenesis. Gli proteins mediate the transcriptional effects of the Sonic hedgehog pathway, which is implicated in up to 25% of human tumors. Here we show that Gli is rapidly destroyed by the proteasome and that mouse basal cell carcinoma induction correlates with Gli protein accumulation. We identify two independent destruction signals in Gli1, D(N) and D(C), and show that removal of these signals stabilizes Gli1 protein and rapidly accelerates tumor formation in transgenic animals. These data argue that control of Gli protein accumulation underlies tumorigenesis and suggest a new avenue for antitumor therapy.

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    • "and CK1 dependent phosphory- lation Huntzicker et al., 2006 Indirect through HDAC "
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    ABSTRACT: The Hedgehog (Hh) signaling pathway plays crucial roles both in embryonic development and in adult stem cell function. The timing, duration and location of Hh signaling activity need to be tightly controlled. Abnormalities of Hh signal transduction lead to birth defects or malignant tumors. Recent data point to ubiquitination-related posttranslational modifications of several key Hh pathway components as an important mechanism of regulation of the Hh pathway. Here we review how ubiquitination regulates the localization, stability and activity of the key Hh signaling components.
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    • "At the level of GLI code, a number of post-translational modifications of GLI proteins play a fundamental role in its control by affecting GLI stability, subcellular localization and DNA binding ability [152–155] (reviewed in [20,40]). To remain focused on the topic of context-dependent GLI activity, we concentrate here on GLI modifications that directly affect the intrinsic GLI transcriptional activity. "
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    ABSTRACT: Canonical Hedgehog (HH) signaling leads to the regulation of the GLI code: the sum of all positive and negative functions of all GLI proteins. In humans, the three GLI factors encode context-dependent activities with GLI1 being mostly an activator and GLI3 often a repressor. Modulation of GLI activity occurs at multiple levels, including by co-factors and by direct modification of GLI structure. Surprisingly, the GLI proteins, and thus the GLI code, is also regulated by multiple inputs beyond HH signaling. In normal development and homeostasis these include a multitude of signaling pathways that regulate proto-oncogenes, which boost positive GLI function, as well as tumor suppressors, which restrict positive GLI activity. In cancer, the acquisition of oncogenic mutations and the loss of tumor suppressors - the oncogenic load - regulates the GLI code towards progressively more activating states. The fine and reversible balance of GLI activating GLIA and GLI repressing GLIR states is lost in cancer. Here, the acquisition of GLIA levels above a given threshold is predicted to lead to advanced malignant stages. In this review we highlight the concepts of the GLI code, the oncogenic load, the context-dependency of GLI action, and different modes of signaling integration such as that of HH and EGF. Targeting the GLI code directly or indirectly promises therapeutic benefits beyond the direct blockade of individual pathways.
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    • "Recent studies demonstrate that it is sufficient to inhibit the growth of PDA through blocking GLI1 activity with RNAi technology or medicinal compounds [19], [45]. GLI1, can be phosphorylated by cAMP-dependent protein kinase (PKA), casein kinase I (CKI) and GSK3β, which in turn results in β-TRCP-mediated protein degradation by the ubiquitin-proteasome system [46], [47], which provides us a direction by targeting GLI1 on PDA therapy. GSK3β is a proline-directed serine-threonine kinase, involved in many cellular processes, such as metabolism, neuronal development, and body pattern formation [48], and GSK3β signaling has also been implicated in mental illness and tumor formation. "
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    ABSTRACT: Hedgehog signaling pathway plays a critical role in the initiation and development of pancreatic ductal adenocarcinoma (PDA) and represents an attractive target for PDA treatment. Lithium, a clinical mood stabilizer for mental disorders, potently inhibits the activity of glycogen synthase kinase 3β (GSK3β) that promotes the ubiquitin-dependent proteasome degradation of GLI1, an important downstream component of hedgehog signaling. Herein, we report that lithium inhibits cell proliferation, blocks G1/S cell-cycle progression, induces cell apoptosis and suppresses tumorigenic potential of PDA cells through down-regulation of the expression and activity of GLI1. Moreover, lithium synergistically enhances the anti-cancer effect of gemcitabine. These findings further our knowledge of mechanisms of action for lithium and provide a potentially new therapeutic strategy for PDA through targeting GLI1.
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