The Experts below are selected from a list of 19806 Experts worldwide ranked by ideXlab platform
Wade Bushman - One of the best experts on this subject based on the ideXlab platform.
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lack of demonstrable autocrine Hedgehog Signaling in human prostate cancer cell lines
The Journal of Urology, 2007Co-Authors: Jingxian Zhang, Robert J Lipinski, Aubie Shaw, Jerry J Gipp, Wade BushmanAbstract:Purpose: Several recent reports highlighted the role of Hedgehog Signaling in prostate cancer. However, the relative contributions of autocrine and paracrine Hedgehog Signaling to tumor growth and progression are unclear. Efforts to model autocrine Signaling for drug development have been hampered by conflicting reports of the presence or absence of autocrine Signaling in established human prostate cancer cell lines.Materials and Methods: We comprehensively characterized the expression of Hedgehog pathway genes in the 3 prostate cancer cell lines LNCaP, PC3 and 22RV1 (American Type Culture Collection, Manassas, Virginia). We also examined their response to Shh ligand and to the Hedgehog pathway inhibitor cyclopamine (Toronto Research Chemicals, Toronto, Ontario, Canada).Results: Expression of Hedgehog ligand, patched and Gli1 in all 3 cell lines was lower than the expression level in normal human prostate tissue. All 3 cell lines showed Hedgehog target gene activation when transfected with an activated fo...
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sonic Hedgehog Signaling regulates the expression of insulin like growth factor binding protein 6 during fetal prostate development
Developmental Dynamics, 2005Co-Authors: Robert J Lipinski, Jerry J Gipp, Crist Cook, Daniel H Barnett, Richard E Peterson, Wade BushmanAbstract:At the onset of ductal morphogenesis in the developing prostate, Shh expression condenses at evaginations of urogenital sinus epithelium and activates Gli transcription factors in the adjacent mesenchyme. Abrogation of Hedgehog Signaling disrupts proper prostatic budding, ductal growth, and branching. We now show that Hedgehog Signaling regulates the expression of insulin-like growth factor binding protein-6 (Igfbp-6) in the developing mouse prostate. Igfbp-6 is a secreted factor that specifically binds insulin-like growth factor-II (IGF-II), prevents its binding to the IGF-I receptor, and is thought to regulate the activity of IGF-II in growth and differentiation. Igfbp-6 is expressed in both the developing and adult prostate. In the urogenital sinus, Igfbp-6 mRNA colocalized with Ptc1 and Gli1 mRNA in the mesenchyme, while Igfbp-6 protein was found in both the mesenchymal and epithelial layers. Exogenous Shh peptide induced expression of Igfbp-6 in the developing prostate while the chemical inhibitor of Hedgehog Signaling, cyclopamine, reduced its expression. These studies show that Igfbp-6 is an actual target of Shh Signaling in the urogenital sinus and provide the first evidence for a linkage between the Hedgehog and IGF Signaling pathways in prostate development.
Jerry J Gipp - One of the best experts on this subject based on the ideXlab platform.
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lack of demonstrable autocrine Hedgehog Signaling in human prostate cancer cell lines
The Journal of Urology, 2007Co-Authors: Jingxian Zhang, Robert J Lipinski, Aubie Shaw, Jerry J Gipp, Wade BushmanAbstract:Purpose: Several recent reports highlighted the role of Hedgehog Signaling in prostate cancer. However, the relative contributions of autocrine and paracrine Hedgehog Signaling to tumor growth and progression are unclear. Efforts to model autocrine Signaling for drug development have been hampered by conflicting reports of the presence or absence of autocrine Signaling in established human prostate cancer cell lines.Materials and Methods: We comprehensively characterized the expression of Hedgehog pathway genes in the 3 prostate cancer cell lines LNCaP, PC3 and 22RV1 (American Type Culture Collection, Manassas, Virginia). We also examined their response to Shh ligand and to the Hedgehog pathway inhibitor cyclopamine (Toronto Research Chemicals, Toronto, Ontario, Canada).Results: Expression of Hedgehog ligand, patched and Gli1 in all 3 cell lines was lower than the expression level in normal human prostate tissue. All 3 cell lines showed Hedgehog target gene activation when transfected with an activated fo...
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sonic Hedgehog Signaling regulates the expression of insulin like growth factor binding protein 6 during fetal prostate development
Developmental Dynamics, 2005Co-Authors: Robert J Lipinski, Jerry J Gipp, Crist Cook, Daniel H Barnett, Richard E Peterson, Wade BushmanAbstract:At the onset of ductal morphogenesis in the developing prostate, Shh expression condenses at evaginations of urogenital sinus epithelium and activates Gli transcription factors in the adjacent mesenchyme. Abrogation of Hedgehog Signaling disrupts proper prostatic budding, ductal growth, and branching. We now show that Hedgehog Signaling regulates the expression of insulin-like growth factor binding protein-6 (Igfbp-6) in the developing mouse prostate. Igfbp-6 is a secreted factor that specifically binds insulin-like growth factor-II (IGF-II), prevents its binding to the IGF-I receptor, and is thought to regulate the activity of IGF-II in growth and differentiation. Igfbp-6 is expressed in both the developing and adult prostate. In the urogenital sinus, Igfbp-6 mRNA colocalized with Ptc1 and Gli1 mRNA in the mesenchyme, while Igfbp-6 protein was found in both the mesenchymal and epithelial layers. Exogenous Shh peptide induced expression of Igfbp-6 in the developing prostate while the chemical inhibitor of Hedgehog Signaling, cyclopamine, reduced its expression. These studies show that Igfbp-6 is an actual target of Shh Signaling in the urogenital sinus and provide the first evidence for a linkage between the Hedgehog and IGF Signaling pathways in prostate development.
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Hedgehog Signaling promotes prostate xenograft tumor growth
Endocrinology, 2004Co-Authors: Lian Fan, Aubie Shaw, Jerry J Gipp, Carmen Pepicelli, Christian C Dibble, Winnie Catbagan, Jodi L Zarycki, Robert Laciak, Marilyn L G Lamm, Alejandro MunozAbstract:During fetal prostate development, Sonic Hedgehog (Shh) expression by the urogenital sinus epithelium activates Gli-1 expression in the adjacent mesenchyme and promotes outgrowth of the nascent ducts. Shh Signaling is down-regulated at the conclusion of prostate ductal development. However, a survey of adult human prostate tissues reveals substantial levels of Shh Signaling in normal, hyperplasic, and malignant prostate tissue. In cancer specimens, the Shh expression is localized to the tumor epithelium, whereas Gli-1 expression is localized to the tumor stroma. Tight correlation between the levels of Shh and Gli-1 expression suggests active Signaling between the tissue layers. To determine whether Shh-Gli-1 Signaling could be functionally important for tumor growth and progression, we performed experiments with the LNCaP xenograft tumor model and demonstrated that: 1) Shh expressed by LNCaP tumor cells activates Gli-1 expression in the tumor stroma, 2) genetically engineered Shh overexpression in LNCaP cells leads to increased tumor stromal Gli-1 expression, and 3) Shh overexpression dramatically accelerates tumor growth. These data suggest that Hedgehog Signaling from prostate cancer cells to the stroma can elicit the expression of paracrine signals, which promote tumor growth. (Endocrinology 145: 3961–3970, 2004)
Christian Siebold - One of the best experts on this subject based on the ideXlab platform.
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sphingomyelin suppresses Hedgehog Signaling by restricting cholesterol accessibility at the ciliary membrane
bioRxiv, 2019Co-Authors: Maia Kinnebrew, Ellen J Iverson, Bhaven B Patel, Ganesh V Pusapati, Jennifer H Kong, Kristen A Johnson, Giovanni Luchetti, Douglas F Covey, Christian Siebold, Arun RadhakrishnanAbstract:Abstract Transmission of the Hedgehog signal across the plasma membrane by Smoothened is proposed to be triggered by its direct interaction with cholesterol. But how is cholesterol, an abundant lipid, regulated tightly enough to control a Signaling system that can cause birth defects and cancer? Using toxin-based sensors that distinguish between distinct pools of cholesterol, we find here that Smoothened activation and Hedgehog Signaling are driven by a biochemically defined fraction of membrane cholesterol, termed accessible cholesterol. Increasing accessible cholesterol levels by depletion of sphingomyelin, which sequesters cholesterol in complexes, potentiates Hedgehog Signaling. By inactivating the transporter-like protein Patched 1, Hedgehog ligands trigger an increase in cholesterol accessibility in the ciliary membrane, the subcellular location for Smoothened Signaling. Thus, compartmentalization of Hedgehog Signaling in the primary cilium may allow cholesterol accessibility to be used as a second messenger to mediate the communication between Patched 1 and Smoothened, without causing collateral effects on other cellular processes.
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cholesterol activates the g protein coupled receptor smoothened to promote Hedgehog Signaling
eLife, 2016Co-Authors: Giovanni Luchetti, Jennifer H Kong, Douglas F Covey, Christian Siebold, Sigrid Nachtergaele, Ria Sircar, Andreas Sagner, Eamon F X Byrne, Rajat RohatgiAbstract:Cells must communicate with each other to coordinate the development of most tissues and organs. Damage to these communication systems is often seen in degenerative disorders and in cancer. The Hedgehog Signaling pathway is one of a handful of these critical systems. Reduced Hedgehog signals can lead to birth defects, while excessive Hedgehog signals can lead to skin and brain cancers. Cells transmit the Hedgehog signal by releasing a protein into their surroundings, where it can influence neighboring cells. Despite years of study, it is not understood how the Hedgehog signal is transmitted from the outside to the inside of a receiving cell. Studies first done in flies and subsequently confirmed in humans have shown that a protein called Smoothened is needed to transmit the Hedgehog signal across the membrane of receiving cells. But it was not known how Smoothened carries out this critical Signaling step to influence gene activation inside the cell and consequently to change cell behavior. Now, Luchetti, Sircar et al. find that cholesterol, an important component of the cell membrane, directly binds to Smoothened and changes its shape so that it can activate Hedgehog Signaling components inside cells. The experiments made use of mouse cells, and the discovery shows that cholesterol may play a previously underappreciated role in cell-to-cell communication. This newly discovered role for cholesterol has implications for diseases, including a unique set of developmental disorders caused by abnormalities in pathways that produce cholesterol in human cells. Furthermore, this unexpected insight into Smoothened’s activity may be clinically important, because Smoothened can cause cancer when mutated and is the target of anti-cancer drugs that are being used in the clinic. Following on from these findings, a major step will be to uncover if and how Hedgehog signals regulate cholesterol to allow Smoothened to transmit these signals across the cell membrane.
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structure and function of the smoothened extracellular domain in vertebrate Hedgehog Signaling
eLife, 2013Co-Authors: Sigrid Nachtergaele, Douglas F Covey, Philip W Ingham, Daniel M Whalen, Laurel K Mydock, Zhonghua Zhao, T Malinauskas, Kathiresan Krishnan, Christian SieboldAbstract:Just over 30 years ago, researchers identified a new Signaling molecule with an important role in the development of fruit flies. Embryos lacking this molecule were thought to resemble a Hedgehog, eventually leading to this cell–cell communication system being designated the “Hedgehog” pathway. This pathway has subsequently been shown to be involved in the development of many other animals, as well as in the repair of damaged tissues in adult organisms. Abnormal Hedgehog Signaling has also been implicated in both human birth defects and in cancers of the skin and the brain. Many such tumors are driven by the unrestrained activation of a membrane-bound protein called Smoothened, which has led to the development and clinical use of small molecules that prevent Hedgehog from activating Smoothened. The existing anti-tumor drugs all bind to the same region of the Smoothened receptor, namely the part that sits within the cell membrane. A second group of molecules, known as oxysterols, can activate Smoothened, but exactly how they do this has been unclear. Now, Nachtergaele et al. have shown that oxysterols bind to a region of the Smoothened receptor that lies outside the cell, and that is rich in the amino acid cysteine. By solving the crystal structure of this part of the receptor from zebrafish, Nachtergaele et al. were able to map the oxysterol binding site at high resolution. This revealed strong similarities between this binding site and those in related receptors belonging to the Wnt Signaling pathway. Deleting the cysteine-rich domain significantly impaired Hedgehog Signaling, as did a new class of small molecule inhibitors designed specifically to target the oxysterol binding site. In addition to providing new insights into the structure and function of the Smoothened receptor, the work of Nachtergaele et al. opens up possibilities for novel therapeutic agents that could be used in the treatment of cancers caused by abnormal Hedgehog Signaling.
Aubie Shaw - One of the best experts on this subject based on the ideXlab platform.
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lack of demonstrable autocrine Hedgehog Signaling in human prostate cancer cell lines
The Journal of Urology, 2007Co-Authors: Jingxian Zhang, Robert J Lipinski, Aubie Shaw, Jerry J Gipp, Wade BushmanAbstract:Purpose: Several recent reports highlighted the role of Hedgehog Signaling in prostate cancer. However, the relative contributions of autocrine and paracrine Hedgehog Signaling to tumor growth and progression are unclear. Efforts to model autocrine Signaling for drug development have been hampered by conflicting reports of the presence or absence of autocrine Signaling in established human prostate cancer cell lines.Materials and Methods: We comprehensively characterized the expression of Hedgehog pathway genes in the 3 prostate cancer cell lines LNCaP, PC3 and 22RV1 (American Type Culture Collection, Manassas, Virginia). We also examined their response to Shh ligand and to the Hedgehog pathway inhibitor cyclopamine (Toronto Research Chemicals, Toronto, Ontario, Canada).Results: Expression of Hedgehog ligand, patched and Gli1 in all 3 cell lines was lower than the expression level in normal human prostate tissue. All 3 cell lines showed Hedgehog target gene activation when transfected with an activated fo...
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Hedgehog Signaling promotes prostate xenograft tumor growth
Endocrinology, 2004Co-Authors: Lian Fan, Aubie Shaw, Jerry J Gipp, Carmen Pepicelli, Christian C Dibble, Winnie Catbagan, Jodi L Zarycki, Robert Laciak, Marilyn L G Lamm, Alejandro MunozAbstract:During fetal prostate development, Sonic Hedgehog (Shh) expression by the urogenital sinus epithelium activates Gli-1 expression in the adjacent mesenchyme and promotes outgrowth of the nascent ducts. Shh Signaling is down-regulated at the conclusion of prostate ductal development. However, a survey of adult human prostate tissues reveals substantial levels of Shh Signaling in normal, hyperplasic, and malignant prostate tissue. In cancer specimens, the Shh expression is localized to the tumor epithelium, whereas Gli-1 expression is localized to the tumor stroma. Tight correlation between the levels of Shh and Gli-1 expression suggests active Signaling between the tissue layers. To determine whether Shh-Gli-1 Signaling could be functionally important for tumor growth and progression, we performed experiments with the LNCaP xenograft tumor model and demonstrated that: 1) Shh expressed by LNCaP tumor cells activates Gli-1 expression in the tumor stroma, 2) genetically engineered Shh overexpression in LNCaP cells leads to increased tumor stromal Gli-1 expression, and 3) Shh overexpression dramatically accelerates tumor growth. These data suggest that Hedgehog Signaling from prostate cancer cells to the stroma can elicit the expression of paracrine signals, which promote tumor growth. (Endocrinology 145: 3961–3970, 2004)
Robert J Lipinski - One of the best experts on this subject based on the ideXlab platform.
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lack of demonstrable autocrine Hedgehog Signaling in human prostate cancer cell lines
The Journal of Urology, 2007Co-Authors: Jingxian Zhang, Robert J Lipinski, Aubie Shaw, Jerry J Gipp, Wade BushmanAbstract:Purpose: Several recent reports highlighted the role of Hedgehog Signaling in prostate cancer. However, the relative contributions of autocrine and paracrine Hedgehog Signaling to tumor growth and progression are unclear. Efforts to model autocrine Signaling for drug development have been hampered by conflicting reports of the presence or absence of autocrine Signaling in established human prostate cancer cell lines.Materials and Methods: We comprehensively characterized the expression of Hedgehog pathway genes in the 3 prostate cancer cell lines LNCaP, PC3 and 22RV1 (American Type Culture Collection, Manassas, Virginia). We also examined their response to Shh ligand and to the Hedgehog pathway inhibitor cyclopamine (Toronto Research Chemicals, Toronto, Ontario, Canada).Results: Expression of Hedgehog ligand, patched and Gli1 in all 3 cell lines was lower than the expression level in normal human prostate tissue. All 3 cell lines showed Hedgehog target gene activation when transfected with an activated fo...
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sonic Hedgehog Signaling regulates the expression of insulin like growth factor binding protein 6 during fetal prostate development
Developmental Dynamics, 2005Co-Authors: Robert J Lipinski, Jerry J Gipp, Crist Cook, Daniel H Barnett, Richard E Peterson, Wade BushmanAbstract:At the onset of ductal morphogenesis in the developing prostate, Shh expression condenses at evaginations of urogenital sinus epithelium and activates Gli transcription factors in the adjacent mesenchyme. Abrogation of Hedgehog Signaling disrupts proper prostatic budding, ductal growth, and branching. We now show that Hedgehog Signaling regulates the expression of insulin-like growth factor binding protein-6 (Igfbp-6) in the developing mouse prostate. Igfbp-6 is a secreted factor that specifically binds insulin-like growth factor-II (IGF-II), prevents its binding to the IGF-I receptor, and is thought to regulate the activity of IGF-II in growth and differentiation. Igfbp-6 is expressed in both the developing and adult prostate. In the urogenital sinus, Igfbp-6 mRNA colocalized with Ptc1 and Gli1 mRNA in the mesenchyme, while Igfbp-6 protein was found in both the mesenchymal and epithelial layers. Exogenous Shh peptide induced expression of Igfbp-6 in the developing prostate while the chemical inhibitor of Hedgehog Signaling, cyclopamine, reduced its expression. These studies show that Igfbp-6 is an actual target of Shh Signaling in the urogenital sinus and provide the first evidence for a linkage between the Hedgehog and IGF Signaling pathways in prostate development.