Hedgehog Gli Signaling in Human Disease

This is a timely primer on how a system of cell communication, Hedgehog-GLI signaling, plays a critical role in human disease and thus provides the background for the development of novel and rational therapies.

Hedgehog Gli Signaling in Human Disease

Hedgehog-GLI Signaling in Human Disease represents the first compilation of up-to-date reviews by top-level scientists in this important field of research. The chapters cover a wide spectrum of related interests, from the molecular bases of morphogen function, to human genetics to cancer research. The aim of the book is to disseminate information on this exciting field, to allow students, scientists and the public in general to gain access current information from research leaders and to provide a book that encompasses different aspects of research showing the fusion of basic research in model systems and medicine. This is a timely primer on how a system of cell communication, Hedgehog-GLI signaling, plays a critical role in human disease and thus provides the background for the development of novel and rational therapies.

Particle Physics and Astrophysics Current Viewpoints

These rather detailed review articles will be of value for many years to come. The book is intended for graduate students and researchers both in particle physics and in astrophysics.

Particle Physics and Astrophysics  Current Viewpoints

Eight carefully written articles on the interactions between the ideas and concepts of particle physics and those of astrophysics make up this book. Two long introductory lectures give a survey of modern concepts in particle physics and in astrophysics and cosmology, stressing features of common interest. The other six contributions deal with the physics of supernova explosions, with black holes, with neutrino oscillations, with the importance of phase transitions for the large-scale structure of the Universe, and with the use of the ideas of quantum gravity for computer simulations. These rather detailed review articles will be of value for many years to come. The book is intended for graduate students and researchers both in particle physics and in astrophysics.

Cancer Stem Cells

Palma, V., and Ruiz I Altaba, A. (2004) Hedgehog-Gli signaling regulates the
behavior of cells with stem cell properties in the developing neocortex.
Development ... 13(1), 113-25. Bale, A. E. (2002) Hedgehog signaling and
human disease.

Cancer Stem Cells

A remarkable paradigm shift has occurred in recent years regarding the biological origins of cancer. The cancer stem cell hypothesis challenged the foundational notions of cancer, and the therapeutic implications have been profound. Compelling evidence indicates that errors in the development of a small subset of adult stem cells can lead to cancer. Only this small sub-population of cells has the inherent ability to form tumours and metastasize. This book discusses the emerging field of cancer stem cell research, with contributions from leading experts on the basic biology, genetic pathways, and potentials for therapeutic targeting of cancer stem cells. It also covers clinical challenges for these new discoveries, namely, that cancer stem cells might be resistant to conventional chemotherapeutic and radiological treatments and may be at the biological core of relapse and therapeutic resistance. This book is an essential concise guide to the latest discoveries and therapies in cancer research.

The Journal of Immunology

Regulation of surface expression of the human pre-T cell receptor complex. ...
Pathways and consequences: Hedgehog signaling in human disease. ... Gli
proteins encode context-dependent positive and negative functions: implications
for ...

The Journal of Immunology


Signal Transduction Pathways Chromatin Structure and Gene Expression Mechanisms as Therapeutic Targets

The mechanism by which activation of the Hedgehog / Patched pathway leads to
carcinogenesis is not entirely clear , but the pathway ... However , it is interesting
that GLI overexpression does not coincide with that of PTCH and is found only in
a small ... Pathway and consequences : hedgehog signaling in human disease .

Signal Transduction Pathways  Chromatin Structure  and Gene Expression Mechanisms as Therapeutic Targets

This volume describes recent findings in the field of fundamental signal transduction mechanisms, including protein kinesis as therapeutic targets as well as applied research toward angiogenesis, apoptosis, and chemopreventive agents.

Stromal epithelial Hedgehog Signaling in Prostate Cancer

Pu , Y. , Huang , L. & Prins , G.S. Sonic hedgehog - patched Gli signaling in the
developing rat prostate gland : lobe ... unidentified amino - terminal domain
regulates transcriptional activity of wild - type and disease - associated human
GLI2 .

Stromal epithelial Hedgehog Signaling in Prostate Cancer


Program and Proceedings

SONIC HEDGEHOG - GLI SIGNALING IN MANTLE CELL LYMPHOMA Katy
Emanuel , Department of Biology , Nebraska Wesleyan ... to cure MCL , a better
understanding of the underlying signaling pathways that regulate MCL disease
progression is clearly needed . ... in the proliferation of MCL cells in vitro using
JVM - 2 , Granta - 519 , Jeko - 1 and Z138 cell lines and human primary MCL
cells .

Program and Proceedings


Cell Signaling and Growth Factors in Development

Two critical periods of Sonic Hedgehog signaling required for the specification of
motor neuron identity . ... 182 Ruiz i Altaba , A . , Gli proteins encode context -
dependent positive and negative functions : implications for development and
disease . ... Identification of a palmitic acid - modified form of human Sonic
hedgehog .

Cell Signaling and Growth Factors in Development

Combining a comprehensive treatment of both embryogenesis and organ development in one reference work, this is the first handbook to be structured according to organ systems. it addresses the functions of all signaling pathways and growth factors important for the development of the embryo and the adult. With its focus on vertebrates, this volume provides a current overview of the molecular communication regulating such processes as cell division, migration, and differentiation. Additionally, sections on developmental disorders and related novel therapeutic strategies highlight applications in molecular medicine.

Regulation of Hedgehog Signal Transduction by Suppressor of Fused Through Multiple Mechanisms

Together this work uncovers important mechanistic insight into the regulation of mammalian Hh signaling and places Su(fu) in a central role as an inhibitory component acting through several mechanisms.

Regulation of Hedgehog Signal Transduction by Suppressor of Fused Through Multiple Mechanisms

During animal development, the Hedgehog (Hh) signal transduction pathway plays a key role in multiple processes including cell fate determination, tissue patterning and morphogenesis. In humans, aberrant Hh signaling has been linked to several genetic disorders and cancers. Hh signaling is ultimately mediated through the activities of the bi-functional Gli/Ci transcription factors. Previously, the mechanism of mammalian Hh signal transduction was extrapolated largely from observations in Drosophila. In this paradigm Suppressor of fused (Su(fu)), a novel protein, inhibits pathway activity by preventing the nuclear accumulation of Ci activator, but is dispensable for development. We have previously cloned mouse Su(fu) and demonstrated it plays a conserved role to inhibit Hh signaling in vitro. Furthermore, mutations in human Su(fu) were found associated with medulloblastoma, implicating Su(fu) as a tumor suppressor. In this thesis, I employ biochemical, cell biological and genetic approaches to investigate the mechanisms through which Su(fu) inhibits activity of the mammalian Gli genes (Glil-3). I find Su(fu) controls the subcellular localization of Gli1 and Gli2 through distinct mechanisms. Moreover, Su(fu) can inhibit Gli activity independent of sequestration, suggesting Su(fu) regulates Gli activity through both nuclear and cytoplasmic means. Loss-of-function analysis in mice revealed Su(fu) is indispensable for embryogenesis, acting as a critical rate-limiting factor to control pathway activity. My genetic and biochemical analyses demonstrated a role for Su(fu) to promote efficient processing of Gli3 into a transcriptional repressor. That Su(fu) promotes Gli repressor formation was unexpected as no similar role has been identified in flies. Significantly, preliminary analyses suggest that Su(fu) controls Gli3 processing through multiple mechanisms. Most notably, Su(fu) appears to facilitate efficient cAMP-dependent protein kinase-mediated phosphorylation of Gli3. Together this work uncovers important mechanistic insight into the regulation of mammalian Hh signaling and places Su(fu) in a central role as an inhibitory component acting through several mechanisms.

The Journal of Cell Biology

Regulation of the Notch target gene Hes-1 by TGFalpha induced Ras/MAPK
signaling in human neuroblastoma cells. Exp. Cell Res. 3 1 0: 2 ... The sonic
hedgehog-patched-gli pathway in human development and disease. Am. J. Hum.
Genet.

The Journal of Cell Biology

No. 2, pt. 2 of November issue each year from v. 19 (1963)-47 (1970) and v. 55 (1972)- contain the Abstracts of papers presented at the Annual Meeting of the American Society for Cell Biology, 3d (1963)-10th (1970) and 12th (1972)-

GLI SOX10 REGULATORY NETWORK I

This dissertation, "Gli-Sox10 Regulatory Network in Neural Crest Development and Hirschsprung Disease Pathogenesis" by Aijia, Liu, 劉艾佳, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to ...

GLI SOX10 REGULATORY NETWORK I

This dissertation, "Gli-Sox10 Regulatory Network in Neural Crest Development and Hirschsprung Disease Pathogenesis" by Aijia, Liu, 劉艾佳, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: In vertebrates, enteric neural crest derived cells (ENCC) undergo coordinated migration, proliferation and differentiation to form enteric nervous system (ENS). Hirschsprung (HSCR, aganglionic megacolon) disease is a complex congenital disease attributed to defective ENS development in human. Previously studies have shown that aberrant Hedgehog (HH) signaling interferes ENCC development and results in disease predisposition. However, the underlying molecular and cellular events remain unclear. In mammals, three effectors, GLI-1, GLI-2 and GLI-3, determine HH signaling output. In this study, deep-targeted sequencing in 20 HSCR patients identified several novel mutations in GLI-1, GLI-2 and GLI-3, where various functional domains of GLI proteins are affected, leading to enhanced GLI activity and perturbed transactivation of Sox10. Endogenous Gli activities in ENS were established utilizing Tg(GBS-GFP) reporter line. In this mouse model, transient activation of Gli signaling was observed only in subpopulations of enteric progenitors and glial progenitors during E11.5 to E12.5 while Gli activity remains low in the differentiated neurons and glial cells, suggesting a casual link between ENCCs differentiation and Gli activation. Suppressor of Fused (Sufu) is a negative regulator of Hh signaling. In concordance with other systems, conditional ablation of Sufu in ENCCs induced high Gli activity which was defined by upregulation of the Hh target genes and increase of the ratio of Gli2 activator (〖Gli2〗 DEGREESA) and Gli3 repressor (〖Gli3〗 DEGREESR). Functional analysis of ENCCs revealed that aberrant Gli activity induces the early onset of neurogenesis and gliogenesis, which finally lead to a significant reduction of neurons and accompanied by an increase of glial cells at distal guts. Intriguingly, The ratio of 〖Gli2〗 DEGREESAand 〖Gli3〗 DEGREESRwas correlated inversely with neuronal versus glial lineage differentiation of ENCCs. In addition to differentiation defects, disrupted chain migration, impaired ENS organizations and defective axonal fasciculation were found in the Sufu mutants. Subsequent mechanistic studies revealed that Gli binds directly to the Sox10 ENS specific enhancers to control its expression level, while Sox10 could also inhibit Sufu expression in ENCCs. Thus, a bi-directional regulatory loop between Sufu-Gli and Sox10 was involved to confer a precise regulation of ENCC differentiation. Collectively, it is the first time identifying GLI mutations in HSCR patients and demonstrating that perturbed SOX10-SUFU-GLI regulatory nexus may contribute to HSCR pathogenesis by interfering neuronal versus glial lineage differentiation and cell migration. Overall, this study described a clinically important signaling cascade implicated in HSCR pathogenesis. Subjects: Hirschsprung's disease - Pathogenesis Neural crest Cellular signal transduction Transcription factors

The Metabolic Molecular Bases of Inherited Disease

... 77 , 350 107 smo Smo Hip Gli family 118 140 , 142 350 148 – 151 338 , 339
340 337 HNF - 3B 142 dpp BMP2 / 4 351 352 296 297 35 ... with all vertebrate
hedgehogs may negatively regulate vertebrate hedgehog signaling zinc finger
transcription factor , mediates hh ... HPE microsigns Gli3 is associated with
human disease transcription factor , required for the development of axial
structures regulates ...

The Metabolic   Molecular Bases of Inherited Disease

Presents clinical, biochemical, and genetic information concerning those metabolic anomalies grouped under inborn errors of metabolism.

Cancer Research

The pathogenesis of BCC involves deregulated Sonic hedgehog signaling ,
leading to activation of the Gli transcription ... In human disease , this is often due
to inactivation mutations in the hedgehog receptor and antagonist , PTCHI ( 6 ) .

Cancer Research


The Basic Science of Oncology

Mullor JL , Sanchez P , Altaba AR : Pathways and consequences : hedgehog
signaling in human disease . Trends Cell Biol ... Ruiz i Altaba A , Sanchez P ,
Dahmane N : Gli and hedgehog in cancer : tumours , embryos and stem cells .
Nat Rev ...

The Basic Science of Oncology

This concise text examines cancer causation and biology as well as the biology underlying cancer treatment. Thoroughly updated and reorganized with five new chapters, the Fourth Edition emphasizes new development in molecular biology, hormone therapy, and the pharmacology of anti-cancer drugs. Features updated coverage of the basic science of radiotherapy and experimental radiation in addition to expansive coverage of new drugs developments.

Inborn Errors of Development

Hedgehog signal transduction via Smoothened association with a cytoplasmic
complex scaffolded by the atypical kinesin , Costal - 2 . Mol Cell 12 ... The sonic
hedgehog - patchedgli pathway in human development and disease . Am J Hum
 ...

Inborn Errors of Development

Honored by the Association of American Publishers as the Best Medical Book of 2004, Inborn Errors is the definitive work on genetically caused abnormalities of human development. Despite the explosion in genetic advances, the causes of two-thirds of all birth defects remain unknown. However, we are on the brink of a revolution in this area, and Inborn Errors is at the forefront. It is the first book to connect the disease-causing gene to its biochemical pathway and to the structural/functional disorder. Mutations of the gene, the clinical picture, genetic counseling and prognosis, and any known treatments are discussed. For medical geneticists, genetic counselors, pediatricians, and developmental biologists, the book is a unique and groundbreaking reference.

The Developing Human

Dellovade T , Romer JT , Curran T , Rubin LJ : The hedgehog pathway and
neurological disorders . Annu Rev ... Stecca B , Ruiz i Altaba A : Brain as a
paradigm of organ growth : Hedgehog - gli signaling in neural stem cells and
brain tumors .

The Developing Human

This resource covers human embryology and teratology, presenting the complex clinical and scientific concepts in a practical way. The 8th edition emphasizes the clinical aspects throughout by using case studies and clinical correlations.

Drugs During Pregnancy and Lactation

... Luo , Donggen ; 136 : 338040h Calcium and oxidative stress : from cell
signaling Yang , Xiongli ( Shanghai Institute of ... Basement membrane laminin ,
many diseases and the aging process , understanding how oxidants alter
through direct ... + signaling can help to understand process of aging and
disease , and follistatin , sonic hedgehog , hepatocyte growth ... 136 : 338043m
Biochemical studies of human DNA polymerase k lineages , for the correct amt .
of the resp . hormones ...

Drugs During Pregnancy and Lactation

The care of pregnant women presents one of the paradoxes of modern medicine. Women usually require little medical intervention during an (uneventful) pregnancy. Conversely, those at high risk of damage to their own health or that of their unborn require the help of appropriate medicinal technology, including drugs. Accordingly, there are two classes of pregnant women, the larger group requires support but not much intervention, while the other needs the full range of diagnostic and therapeutic measures applied in any other branch of medicine. This book presents the current state of knowledge about drugs in pregnancy. In each chapter information is presented separately for two different aspects of the problem seeking a drug appropriate for prescription during pregnancy, and assessing the risk of a drug when exposure has already taken place. Practising clinicians who prescribe medicinal products to women who are, or who may become, pregnant, will find this volume an invaluable reference.

The Role of Shh dependent Gli Activator and Repressor Functions in Epidermal Development and Disease microform

Tightly regulated Sonic hedgehog (Shh) signaling in the skin is required for epidermal growth during hair follicle development, but unregulated responses result in common human skin tumors.

The Role of Shh dependent Gli Activator and Repressor Functions in Epidermal Development and Disease  microform

Tightly regulated Sonic hedgehog (Shh) signaling in the skin is required for epidermal growth during hair follicle development, but unregulated responses result in common human skin tumors. How Hh signals are mediated in target cells is determined by the combined activities of members of the Gli family of zinc finger transcription factors. The role of Gli transcription factors during skin development and disease was previously unknown. Using a genetic approach complementing loss-of-function and gain-of-function mouse mutants, we have been able to dissect temporal and spatial requirements for Shh signaling in the skin. During hair follicle morphogenesis, Shh signaling is primarily required by the epidermis to promote the proliferation of epidermal progenitors. Two important functions of Shh signaling are required for mitogenic responses to occur; (1) promoting the generation of Gli activators, especially Gli2ACT and (2) inhibiting the generation of Gli repressors, primarily Gli3REP. The summation of these Gli activities determines the transcriptional activity of target genes and ultimately, the decision to enter the cell cycle and proliferate. These studies have revealed novel Gli-dependent regulation of a transcriptional hierarchy of key cell cycle regulators, including the D-type cyclins, N-myc and E2Fs. Furthermore, it has unveiled functional differences in how these target genes are regulated by Gli functions. In Shh;Gli3 double mutants, the expression of early cell cycle markers was derepressed, but induction of later regulators, namely activator E2Fs, could not be induced without GliACT, and no robust proliferative responses were observed. These results suggest that Shh signaling controls multiple levels of the cell cycle to ensure that proliferative responses are restricted in time and space to regions of high Hh signal. The Hh-dependent balance of Gli activator and repressor functions also plays a key role in limiting proliferative responses to adult hair follicles at the telogen-anagen transition. Disturbing this balance, either by increasing the magnitude of Hh responses transiently at anagen in K5Cre;Z/APGli2 mice or extending Hh responses independently of the hair cycle in K5Cre;Z/APDeltaNGli2 mice, is sufficient to overwhelm endogenous regulation. These changes disrupt epidermal homeostasis, triggering hyperproliferative responses and tumors in transgenic skin.

Molecular Biology of the Cell

Gli - type zinc finger proteins as bipotential transducers of Hedgehog signaling .
Differentiation 70 , 69 ... G . L . 13 mutations in human disorders mimic
Drosophila cubitus interruptus protein functions and localization . Proc . Natl .
Acad . Sci .

Molecular Biology of the Cell