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6, 7 GLI1 and GLI2 act as the main mediators of the HH signaling in cancer by controlling the expression of target genes involved in proliferation, survival, stemness and metastasis. Consequently, active SMO triggers an intracellular signaling cascade leading to the formation of activating forms of the GLI zinc finger transcription factors GLI2 and GLI3, which directly activate GLI1. 4, 5 Canonical HH pathway activation is initiated by the binding of HH ligands to the transmembrane protein Patched 1 (PTCH1), which becomes internalized and relieves its inhibition on the transmembrane protein Smoothened (SMO).
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3 Aberrant activation of the HH pathway has been implicated in several types of cancer, including those of the skin. The Hedgehog-GLI (HH-GLI) signaling is critical for growth and patterning of numerous tissues during embryogenesis and early development, 1, 2 but it is mostly quiescent in the adult, where it mainly regulates stem cell behavior. These findings open a novel therapeutic approach for human melanomas and, possibly, other cancer types expressing WIP1 and with activated HH pathway. Overall, our data uncover a role for WIP1 in modulating the activity of GLI1 and in sustaining cancer cell growth and cancer stem cell self-renewal induced by activation of the HH pathway.
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Pharmacological blockade of the HH pathway with the SMOOTHENED antagonist cyclopamine acts synergistically with inhibition of WIP1 in reducing growth of melanoma and breast cancer cells in vitro. Functionally, we find that WIP1 is required for melanoma and breast cancer cell proliferation and self-renewal in vitro and melanoma xenograft growth induced by activation of the HH signaling. Modulation of the transcriptional activity of GLI1 by WIP1 depends on the latter’s phosphatase activity and, remarkably, does not require p53, a known WIP1 target. We also find that WIP1 and GLI1 are in a complex. Mechanistically, WIP1 enhances the function of GLI1 by increasing its transcriptional activity, nuclear localization and protein stability, but not of GLI2 nor GLI3.
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Here, we show that WIP1 (or PPM1D), an oncogenic phosphatase amplified/overexpressed in several types of human cancer, is a positive modulator of the HH signaling. Phosphorylation events have been shown to regulate the activity of the GLI transcription factors, the final effectors of the HH-GLI signaling pathway. Continued abuse of our services will cause your IP address to be blocked indefinitely.The Hedgehog-GLI (HH-GLI) signaling plays a critical role in controlling growth and tissue patterning during embryogenesis and is implicated in a variety of human malignancies, including those of the skin. Please fill out the CAPTCHA below and then click the button to indicate that you agree to these terms. If you wish to be unblocked, you must agree that you will take immediate steps to rectify this issue. If you do not understand what is causing this behavior, please contact us here. If you promise to stop (by clicking the Agree button below), we'll unblock your connection for now, but we will immediately re-block it if we detect additional bad behavior. Overusing our search engine with a very large number of searches in a very short amount of time.Using a badly configured (or badly written) browser add-on for blocking content.Running a "scraper" or "downloader" program that either does not identify itself or uses fake headers to elude detection.Using a script or add-on that scans GameFAQs for box and screen images (such as an emulator front-end), while overloading our search engine.There is no official GameFAQs app, and we do not support nor have any contact with the makers of these unofficial apps. Continued use of these apps may cause your IP to be blocked indefinitely. This triggers our anti-spambot measures, which are designed to stop automated systems from flooding the site with traffic. Some unofficial phone apps appear to be using GameFAQs as a back-end, but they do not behave like a real web browser does.Using GameFAQs regularly with these browsers can cause temporary and even permanent IP blocks due to these additional requests. If you are using Maxthon or Brave as a browser, or have installed the Ghostery add-on, you should know that these programs send extra traffic to our servers for every page on the site that you browse.The most common causes of this issue are: Your IP address has been temporarily blocked due to a large number of HTTP requests.