Misactivation of Hedgehog signaling causes inherited and sporadic cancers

Raleigh, David R.; Reiter, Jeremy F.

doi:10.1172/jci120850

Cited by 75 publications

(57 citation statements)

References 192 publications

(219 reference statements)

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“…These genetic instabilities were closely related to the Hh signaling pathway. Indeed, mutations in the Hh signaling pathway lead to genetic instability and various cancers [ 39 ]. For example, the PTCH1 germline mutation causes many BCCs in patients and, rarely, rhabdomyosarcoma (RMS).…”

Section: Genomic Instabilitymentioning

confidence: 99%

“…According to the WHO classification, there are five organizational types [ 75 ]: classic medulloblastoma, anaplastic medulloblastoma, large cell medulloblastoma, fibrogenic/nodular medulloblastoma, medulloblastoma, and extensive nodule formation. Approximately 5% of children with basal cell nevus syndrome develop medulloblastoma (undifferentiated neuroectodermal tumor: PNET) [ 39 ], which is often fibrogenic and medulloblastoma in GS [ 76 ]. The peak of onset is at the age of 2 and is characterized by onset at a young age [ 77 ].…”

Section: Tumorsmentioning

confidence: 99%

“…Cardiac and ovarian fibromas occur in approximately 2% and 20% of females, respectively [ 6 , 94 ]. Ovarian fibromas or cardiac fibromas are usually present at birth or occur soon after [ 39 ]. Cardiac fibromas can be asymptomatic or can cause arrhythmia or obstruction of cardiac flow.…”

Section: Tumorsmentioning

confidence: 99%

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Gorlin Syndrome: Recent Advances in Genetic Testing and Molecular and Cellular Biological Research

Onodera

Nakamura

2020

IJMS

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Gorlin syndrome is a skeletal disorder caused by a gain of function mutation in Hedgehog (Hh) signaling. The Hh family comprises of many signaling mediators, which, through complex mechanisms, play several important roles in various stages of development. The Hh information pathway is essential for bone tissue development. It is also the major driver gene in the development of basal cell carcinoma and medulloblastoma. In this review, we first present the recent advances in Gorlin syndrome research, in particular, the signaling mediators of the Hh pathway and their functions at the genetic level. Then, we discuss the phenotypes of mutant mice and Hh signaling-related molecules in humans revealed by studies using induced pluripotent stem cells.

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Section: Genomic Instabilitymentioning

confidence: 99%

Section: Tumorsmentioning

confidence: 99%

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Gorlin Syndrome: Recent Advances in Genetic Testing and Molecular and Cellular Biological Research

Onodera

Nakamura

2020

IJMS

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“…Hh signaling during embryogenesis results in birth defects whereas increased Hh 23 signaling leads to tumors, highlighting the importance of the pathway and its regulation 24 (Raleigh et al 2019). 25…”

Section: Introductionmentioning

confidence: 99%

ARL13B regulates Sonic Hedgehog signaling from outside primary cilia

Gigante

Taylor

Ivanova

et al. 2019

Preprint

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ARL13B is a regulatory GTPase highly enriched in cilia. Complete loss of Arl13b 1 disrupts cilia architecture, protein trafficking and Sonic hedgehog signaling. To 2 determine whether ARL13B is required within cilia, we knocked in a cilia-excluded 3 variant of ARL13B (V358A) and showed it retains all known biochemical function. We 4 found that ARL13B V358A protein was expressed but could not be detected in cilia, even 5 when retrograde ciliary transport was blocked. We showed Arl13b V358A/V358A mice are 6 viable and fertile with normal Shh signal transduction. However, in contrast to wild type 7 cilia, Arl13b V358A/V358A cells displayed short cilia and lacked ciliary ARL3 and INPP5E. 8These data indicate that ARL13B's role within cilia can be uncoupled from its function 9 outside of cilia. Furthermore, these data imply that the cilia defects upon complete 10 absence of ARL13B do not underlie the alterations in Shh transduction, which is 11 unexpected given the requirement of cilia for Shh transduction. 12

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“…In addition to their roles during embryogenesis, HH ligands also function in paracrine signaling networks to regulate tissue homeostasis and regenerative responses in adults . Mutations in HH pathway components that increase signaling strength can drive tumorigenesis, and two HH pathway inhibitors are currently used in the clinic to treat basal cell carcinoma (Raleigh and Reiter, 2019).…”

Section: Introductionmentioning

confidence: 99%

Biochemical mechanisms of vertebrate hedgehog signaling

2019

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Signaling pathways that mediate cell-cell communication are essential for collective cell behaviors in multicellular systems. The hedgehog (HH) pathway, first discovered and elucidated in Drosophila, is one of these iconic signaling systems that plays many roles during embryogenesis and in adults; abnormal HH signaling can lead to birth defects and cancer. We review recent structural and biochemical studies that have advanced our understanding of the vertebrate HH pathway, focusing on the mechanisms by which the HH signal is received by patched on target cells, transduced across the cell membrane by smoothened, and transmitted to the nucleus by GLI proteins to influence gene-expression programs.

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Misactivation of Hedgehog signaling causes inherited and sporadic cancers

Cited by 75 publications

References 192 publications

Gorlin Syndrome: Recent Advances in Genetic Testing and Molecular and Cellular Biological Research

Gorlin Syndrome: Recent Advances in Genetic Testing and Molecular and Cellular Biological Research

ARL13B regulates Sonic Hedgehog signaling from outside primary cilia

Biochemical mechanisms of vertebrate hedgehog signaling

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