The Gli code: an information nexus regulating cell fate, stemness and cancer

Altaba, Ariel Ruiz i; Mas, Christophe; Stecca, Barbara

doi:10.1016/j.tcb.2007.06.007

Cited by 343 publications

(378 citation statements)

References 104 publications

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“…The GLI transcription factors are the main mediators of the Hedgehog (HH) signal and are important during development, tissue homeostasis, regeneration and stem cell maintenance (reviewed in Beachy et al, 2004;Ingham and McMahon, 2001; Pasca di Magliano and Hebrok, 2003;Ruiz i Altaba et al, 2007). The importance of the HH/GLI pathway and its components in regulating proliferation and differentiation is reflected in the growing number of malignancies of skin, brain, pancreas, prostate and lung, which have been linked to ectopic expression of activator GLI proteins (reviewed in Evangelista et al, 2006;Hebrok, 2003;Pasca di Magliano and Hebrok, 2003;Rubin and de Sauvage, 2006;Ruiz i Altaba et al, 2007;Stecca and Ruiz i Altaba, 2002;Vezina and Bushman, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…The importance of the HH/GLI pathway and its components in regulating proliferation and differentiation is reflected in the growing number of malignancies of skin, brain, pancreas, prostate and lung, which have been linked to ectopic expression of activator GLI proteins (reviewed in Evangelista et al, 2006;Hebrok, 2003;Pasca di Magliano and Hebrok, 2003;Rubin and de Sauvage, 2006;Ruiz i Altaba et al, 2007;Stecca and Ruiz i Altaba, 2002;Vezina and Bushman, 2007). Normally, binding of HH to its receptor PTCH leads to the stabilization and activation of full-length GLI proteins (GLIact) through the transmembrane signal transducer smoothened (SMOH).…”

Section: Introductionmentioning

confidence: 99%

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Cooperation between GLI and JUN enhances transcription of JUN and selected GLI target genes

et al. 2009

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Sustained Hedgehog (HH) signaling is implicated in basal cell carcinoma of the skin and other types of cancer. Here we show that GLI1 and GLI2, the main transcriptional activators of the HH pathway, directly regulate expression of the activator protein 1 (AP-1) family member JUN, a transcription factor controlling keratinocyte proliferation and skin homeostasis. Activation of the JUN promoter by GLI is dependent on a GLI-binding site and the AP-1 sites known to be involved in self-activation of JUN. Transcription of JUN is greatly enhanced in the presence of GLI and requires activated JUN protein.GLI2act is a more potent activator than GLI1 in these experiments and physical interaction with phosphorylated JUN was only detected for GLI2act. The synergistic effect of GLI and JUN extends to the activation of further GLI target genes as shown by shRNA-mediated knockdown of JUN in human keratinocytes. Some of these cooperatively activated genes are involved in cell-cycle progression, which is consistent with a significant reduction of the proliferative potential of GLI in the absence of JUN. These results suggest a novel connection between HH/GLI pathway activity and JUN, which may contribute to the oncogenic activity of HH/GLI signaling in skin.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cooperation between GLI and JUN enhances transcription of JUN and selected GLI target genes

et al. 2009

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“…Mutations in various components of its signaling pathway frequently occur in tumors originated from the skin, cerebellum and skeletal muscle (Ruiz i Altaba et al, 2002), and abnormal pathway activity is associated with a subset of lung, digestive tract, pancreatic and prostate cancers (Beachy et al, 2004). Shh signaling follows an unusual logic, in that binding of the ligand to its receptor, Patched (Ptch), alleviates an inhibition from Ptch on a downstream membrane protein, Smoothened (Smo), which ultimately activates target genes through a family of three Gli transcription factors (Jacob and Lum, 2007; Ruiz i Altaba et al, 2007;Wang et al, 2007). The Gli proteins recognize a common cis-element via a zinc-finger DNA binding domain, and can either activate or repress transcription depending on whether Gli2 and Gli3 are processed by a proteolytic cleavage that converts them into repressors.…”

Section: Introductionmentioning

confidence: 99%

“…Gli1, a target of Shh signaling itself, does not undergo this cleavage event, and therefore always acts as an activator. Expression of Gli1 is elevated in a variety of tumors as the consequence of Shh pathway activation, and ectopic expression of Gli1 and Gli2 results in skin cancers in mice (Ruiz i Altaba et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin–proteasome pathway

2008

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Sustained Sonic hedgehog (Shh) pathway activity is associated with tumorigenesis in a wide variety of tissues. Mutational inactivation of Shh receptor Patched (Ptch) and a downstream gene Suppressor of fused (Sufu), both of which are negative regulators of the pathway, increases susceptibility to cerebellum cancer in humans and mice. Sufu is a binding partner of Shh pathway transcription factor Gli. Recent data indicate that inactivation of Sufu, through either gene targeting in mice or RNAi-mediated silencing in cultured fibroblasts, is sufficient to turn on Shh target gene expression. Here, we report that Sufu is degraded rapidly in certain cancer cells and we show that Shh signaling promotes ubiquitination of Sufu, which leads to its destruction in the proteasomes. We identified an ubiquitin attachment site on K257 of Sufu, and showed that Sufu-K257R mutant is more potent as a transcription repressor and cell growth inhibitor because of increased stability. These results indicate that Shh signaling regulates Sufu activity by inducing its turnover via the ubiquitin-proteasome system.

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“…SHH ligand mRNA was weakly expressed in GICs, a finding that partially explained the higher expression of GLI3 compared with GLI1; although transcription of GLI1 is silenced in the absence of SHH ligand, GLI3 can still be expressed (44). Furthermore, inhibition of GLI3 has been shown to revert the antiproliferative and proapoptotic effects of cyclopamine, which were thereby mediated (19).…”

Section: Discussionmentioning

confidence: 99%

Selective Release of a Cyclopamine Glucuronide Prodrug toward Stem-like Cancer Cell Inhibition in Glioblastoma

Balbous

Renoux

Cortes

et al. 2014

Molecular Cancer Therapeutics

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Recent data suggest that inhibition of the Hedgehog pathway could be a therapeutic target for glioblastoma. Alkaloid cyclopamine inhibits Hedgehog signaling, depleting stem-like cancer cells derived from glioblastoma. However, this compound is toxic for somatic stem cells, preventing its use for clinical applications. In this study, we tested a derivatization product of cyclopamine in the form of cyclopamine glucuronide prodrug (CGP-2). This compound was used in vitro and in vivo toward glioblastoma-initiating cells (GIC). Results obtained in vitro indicate that CGP-2 is active only in the presence of b-glucuronidase, an enzyme detected in high levels in necrotic areas of glioblastomas. CGP-2 decreased proliferation and inhibited the self-renewal of all GIC lines tested. Hedgehog pathway blockade by 10 mmol/L of CGP-2 induced a 99% inhibition of clonogenicity on GICs, similar to cyclopamine treatment. Combination of CGP-2 with radiation decreased clonogenic survival in all GIC lines compared with CGP-2 alone. In a subcutaneous glioblastoma xenograft model, a two-week CGP-2 treatment prevented tumor growth with 75% inhibition at 8 weeks, and this inhibition was still significant after 14 weeks. Unlike cyclopamine, CGP-2 had no detectable toxic effects in intestinal crypts. Our study suggests that inhibition of the Hedgehog pathway with CGP-2 is more effective than conventional temozolomide adjuvant, with much lower concentrations, and seems to be an effective therapeutic strategy for targeting GICs. Mol Cancer Ther; 13(9); 2159-69. Ó2014 AACR.

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The Gli code: an information nexus regulating cell fate, stemness and cancer

Cited by 343 publications

References 104 publications

Cooperation between GLI and JUN enhances transcription of JUN and selected GLI target genes

Cooperation between GLI and JUN enhances transcription of JUN and selected GLI target genes

Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin–proteasome pathway

Selective Release of a Cyclopamine Glucuronide Prodrug toward Stem-like Cancer Cell Inhibition in Glioblastoma

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