Dysgerminoma with a Somatic Exon 17 KIT Mutation and SHH Pathway Activation in a Girl with Turner Syndrome

This article reports a case of a 7-year-old girl with Turner syndrome, treated with growth hormone (GH), who developed ovarian dysgerminoma. The patient karyotype was mosaic for chromosome Xq deletion: 46,X,del(X)(q22)/45,X. No Y chromosome sequences were present. Molecular studies revealed the presence of a driving mutation in exon 17 of the KIT gene in the neoplastic tissue, as well as Sonic-hedgehog (SHH) pathway activation at the protein level. The patient responded well to chemotherapy and remained in complete remission. This is the first case of dysgerminoma in a Turner syndrome patient with such oncogenic pathway.

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Patched1–ArhGAP36–PKA–Inversin axis determines the ciliary translocation of Smoothened for Sonic Hedgehog pathway activation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1804042116 ◽

2018 ◽

Vol 116 (3) ◽

pp. 874-879 ◽

Cited By ~ 11

Author(s):

Boyan Zhang ◽

Tenghan Zhuang ◽

Qiaoyu Lin ◽

Biying Yang ◽

Xiaowei Xu ◽

...

Keyword(s):

Cell Proliferation ◽

Sonic Hedgehog ◽

Initial Step ◽

Negative Regulator ◽

Individual Development ◽

Sonic Hedgehog Pathway ◽

Shh Pathway ◽

Pathway Activation ◽

Mother Centriole ◽

Signaling Activation

The Sonic Hedgehog (Shh) pathway conducts primarily in the primary cilium and plays important roles in cell proliferation, individual development, and tumorigenesis. Shh ligand binding with its ciliary membrane-localized transmembrane receptor Patched1 results in the removal of Patched1 from and the translocation of the transmembrane oncoprotein Smoothened into the cilium, leading to Shh signaling activation. However, how these processes are coupled remains unknown. Here, we show that the Patched1–ArhGAP36–PKA–Inversin axis determines the ciliary translocation of Smoothened. We find that Patched1 interacts with and stabilizes the PKA negative regulator ArhGAP36 to the centrosome. Activating the Shh pathway results in the removal of ArhGAP36 from the mother centriole and the centrosomal PKA accumulation. This PKA then phosphorylates Inversin and promotes its interaction with and the ciliary translocation of Smoothened. Knockdown of Inversin disrupts the ciliary translocation of Smoothened and Shh pathway activation. These findings reveal a regulatory molecular mechanism for the initial step of Shh pathway activation.

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Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception

eLife ◽

10.7554/elife.02555 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 56

Author(s):

Shen Yue ◽

Liu-Ya Tang ◽

Ying Tang ◽

Yi Tang ◽

Qiu-Hong Shen ◽

...

Keyword(s):

Sonic Hedgehog ◽

Feedback Loop ◽

Hect Domain ◽

E3 Ligases ◽

Caveolin 1 ◽

Shh Pathway ◽

Sorting Signals ◽

Pathway Activation ◽

Endocytic Sorting ◽

Hedgehog Signal

Cell surface reception of Sonic hedgehog (Shh) must ensure that the graded morphogenic signal is interpreted accordingly in neighboring cells to specify tissue patterns during development. Here, we report endocytic sorting signals for the receptor Patched1 (Ptch1), comprising two ‘PPXY’ motifs, that direct it to degradation in lysosomes. These signals are recognized by two HECT-domain ubiquitin E3 ligases, Smurf1 and Smurf2, which are induced by Shh and become enriched in Caveolin-1 lipid rafts in association with Ptch1. Smurf-mediated endocytic turnover of Ptch1 is essential for its clearance from the primary cilium and pathway activation. Removal of both Smurfs completely abolishes the ability of Shh to sustain the proliferation of postnatal granule cell precursors in the cerebellum. These findings reveal a novel step in the Shh pathway activation as part of the Ptch1 negative feedback loop that precisely controls the signaling output in response to Shh gradient signal.

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Sonic Hedgehog Opposes Epithelial Cell Cycle Arrest

The Journal of Cell Biology ◽

10.1083/jcb.147.1.71 ◽

1999 ◽

Vol 147 (1) ◽

pp. 71-76 ◽

Cited By ~ 99

Author(s):

Hongran Fan ◽

Paul A. Khavari

Keyword(s):

Cell Cycle ◽

Epithelial Cell ◽

Cell Cycle Arrest ◽

Sonic Hedgehog ◽

Growth Arrest ◽

Epidermal Hyperplasia ◽

Shh Pathway ◽

Cycle Arrest ◽

Pathway Activation

Stratified epithelium displays an equilibrium between proliferation and cell cycle arrest, a balance that is disrupted in basal cell carcinoma (BCC). Sonic hedgehog (Shh) pathway activation appears sufficient to induce BCC, however, the way it does so is unknown. Shh-induced epidermal hyperplasia is accompanied by continued cell proliferation in normally growth arrested suprabasal cells in vivo. Shh-expressing cells fail to exit S and G2/M phases in response to calcium-induced differentiation and also resist exhaustion of replicative growth capacity. In addition, Shh blocks p21CIP1/WAF1-induced growth arrest. These data indicate that Shh promotes neoplasia by opposing normal stimuli for epithelial cell cycle arrest.

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Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons

Molecular Biology of the Cell ◽

10.1091/mbc.e16-07-0553 ◽

2017 ◽

Vol 28 (3) ◽

pp. 387-395 ◽

Cited By ~ 18

Author(s):

Pamela J. Yao ◽

Uri Manor ◽

Ronald S. Petralia ◽

Rebecca D. Brose ◽

Ryan T. Y. Wu ◽

...

Keyword(s):

Sonic Hedgehog ◽

Hippocampal Neurons ◽

Mitochondrial Fission ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Shh Signaling ◽

Shh Pathway ◽

Pathway Activation ◽

Peptide Hydrogen ◽

And Function

Mitochondria are essential organelles whose biogenesis, structure, and function are regulated by many signaling pathways. We present evidence that, in hippocampal neurons, activation of the Sonic hedgehog (Shh) signaling pathway affects multiple aspects of mitochondria. Mitochondrial mass was increased significantly in neurons treated with Shh. Using biochemical and fluorescence imaging analyses, we show that Shh signaling activity reduces mitochondrial fission and promotes mitochondrial elongation, at least in part, via suppression of the mitochondrial fission protein dynamin-like GTPase Drp1. Mitochondria from Shh-treated neurons were more electron-dense, as revealed by electron microscopy, and had higher membrane potential and respiratory activity. We further show that Shh protects neurons against a variety of stresses, including the mitochondrial poison rotenone, amyloid β-peptide, hydrogen peroxide, and high levels of glutamate. Collectively our data suggest a link between Shh pathway activity and the physiological properties of mitochondria in hippocampal neurons.

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Effect of Sonic hedgehog activation on CXCR7 expression and CXCR4 signaling in medulloblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e13537 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e13537-e13537

Author(s):

Stacey Anne Ward ◽

Rajarshi Sengupta ◽

Joshua Rubin

Keyword(s):

Tumor Cells ◽

Sonic Hedgehog ◽

Granule Cells ◽

Single Cells ◽

Primary Cultures ◽

Normal Cells ◽

Cxcr4 Signaling ◽

Shh Pathway ◽

Pathway Activation ◽

Surface Localization

e13537 Background: Stratification of pediatric medullolastoma into molecular subtypes elevates hopes that subtype-specific therapy can be more efficacious and less toxic. To realize this goal, the molecular targets that distinguish each subtype must be defined. We found that Sonic hedgehog (Shh)-subtype medulloblastoma can be further divided by CXCR4 expression and that CXCR4 inhibition has potent anti-tumor effects. Here we present data that Shh regulates CXCR4 activity through CXCR7, whose differential expression between normal granule cells and medulloblastoma cells makes its function an ideal therapeutic target. Methods: Single-cell suspensions were plated with or without Shh or cyclopamine followed by treatment with CXCL12. SmoA1 brain tumors were dissociated into single cells and transplanted into nude mice and treated with vehicle, AMD3100, GDC-0449, or both. Tumors were measured and harvested at the conclusion of treatment. Results: Using primary cultures of Shh-driven medulloblastoma we found that Shh activation enhances CXCR4 surface localization and promotes CXCL12-induced signaling, similar to effects of Shh on normal granule cells. We evaluated expression of CXCR4 internalization regulators and found that Shh activation altered the levels of GRKs, arrestins and CXCR7. Among these, CXCR7 expression exhibited the greatest differential response to Shh pathway activation between normal cells and medulloblastoma: CXCR7 expression was highly expressed in normal cells despite Shh effects, but almost completely absent in tumor cells. Conclusions: We conclude that activation of the Shh pathway in medulloblastomas promotes CXCR4 surface localization through inhibition of internalization mediators. This cross-talk is also evident in developing GPCs but with one notable difference: CXCR7 expression (high in normal cells, absent in tumor cells). This distinction suggests that CXCR7 antagonists, which are moving towards clinical trials, may be detrimental to normal cerebellar development and inactive against medulloblastoma. We propose that restoring CXCR7 activity would have negligible effects on granule cells and potently block CXCR4 function in medulloblastoma.

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Ixazomib Improves Bone Remodeling and Counteracts Sonic Hedgehog Signaling Inhibition Mediated by Myeloma Cells

Cancers ◽

10.3390/cancers12020323 ◽

2020 ◽

Vol 12 (2) ◽

pp. 323 ◽

Cited By ~ 5

Author(s):

Daniele Tibullo ◽

Anna Longo ◽

Nunzio Vicario ◽

Alessandra Romano ◽

Alessandro Barbato ◽

...

Keyword(s):

Osteogenic Differentiation ◽

Bone Remodeling ◽

Sonic Hedgehog ◽

Bone Disease ◽

Human Mscs ◽

Bone Homeostasis ◽

Shh Signaling ◽

Shh Pathway ◽

Pathway Activation ◽

Osteolytic Bone Disease

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of plasma cells (PC) in the bone marrow (BM), leading to bone loss and BM failure. Osteolytic bone disease is a common manifestation observed in MM patients and represents the most severe cause of morbidity, leading to progressive skeletal damage and disabilities. Pathogenetic mechanisms of MM bone disease are closely linked to PCs and osteoclast (OCs) hyperactivity, coupled with defective osteoblasts (OBs) function that is unable to counteract bone resorption. The aim of the present study was to investigate the effects of Ixazomib, a third-generation proteasome inhibitor, on osteoclastogenesis and osteogenic differentiation. We found that Ixazomib was able to reduce differentiation of human monocytes into OCs and to inhibit the expression of OC markers when added to the OC medium. Concurrently, Ixazomib was able to stimulate osteogenic differentiation of human mesenchymal stromal cells (MSCs), increasing osteogenic markers, either alone or in combination with the osteogenic medium. Given the key role of Sonic Hedgehog (SHH) signaling in bone homeostasis, we further investigated Ixazomib-induced SHH pathway activation. This set of experiments showed that Ixazomib, but not Bortezomib, was able to bind the Smoothened (SMO) receptor leading to nuclear translocation of GLI1 in human MSCs. Moreover, we demonstrated that PCs act as GLI1 suppressors on MSCs, thus reducing the potential of MSCs to differentiate in OBs. In conclusion, our data demonstrated that Ixazomib regulates bone remodeling by decreasing osteoclastogenesis and prompting osteoblast differentiation via the canonical SHH signaling pathway activation, thus, representing a promising therapeutic option to improve the complex pathological condition of MM patients.

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Lhx2 is a progenitor-intrinsic modulator of Sonic Hedgehog signaling during early retinal neurogenesis

10.1101/2021.04.24.441277 ◽

2021 ◽

Author(s):

Xiaodong Li ◽

Patrick J Gordon ◽

John A Gaynes ◽

Alexandra W Fuller ◽

Randy Ringuette ◽

...

Keyword(s):

Transcription Factors ◽

Signaling Pathways ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Sonic Hedgehog Signaling ◽

Shh Signaling ◽

Downstream Targets ◽

Shh Pathway ◽

Pathway Activation ◽

Retinal Neurogenesis

An important question in organogenesis is how tissue-specific transcription factors interact with signaling pathways. In some cases, transcription factors define the context for how signaling pathways elicit tissue- or cell-specific responses, and in others, they influence signaling through transcriptional regulation of signaling components or accessory factors. We previously showed that during optic vesicle patterning, the Lim-homeodomain transcription factor Lhx2 has a contextual role by linking the Sonic Hedgehog (Shh) pathway to downstream targets without regulating the pathway itself. Here, we show that during early retinal neurogenesis, Lhx2 is a multilevel regulator of Shh signaling. Specifically, Lhx2 acts cell autonomously to control the expression of pathway genes required for efficient activation and maintenance of signaling in retinal progenitor cells. The Shh co-receptors Cdon and Gas1 are candidate direct targets of Lhx2 that mediate pathway activation, whereas Lhx2 directly or indirectly promotes the expression of other pathway components important for activation and sustained signaling. We also provide genetic evidence suggesting that Lhx2 has a contextual role by linking the Shh pathway to downstream targets. Through these interactions, Lhx2 establishes the competence for Shh signaling in retinal progenitors and the context for the pathway to promote early retinal neurogenesis. The temporally distinct interactions between Lhx2 and the Shh pathway in retinal development illustrate how transcription factors and signaling pathways adapt to meet stage-dependent requirements of tissue formation.

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Sonic Hedgehog and Triiodothyronine Pathway Interact in Mouse Embryonic Neural Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21103672 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3672

Author(s):

Pavel Ostasov ◽

Jan Tuma ◽

Pavel Pitule ◽

Jiri Moravec ◽

Zbynek Houdek ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Sonic Hedgehog ◽

Shh Pathway ◽

Proliferation Activity ◽

The Central Nervous System ◽

Beta Gene ◽

Potential Tool ◽

Receptor Beta ◽

Transplantation Therapy

Neural stem cells are fundamental to development of the central nervous system (CNS)—as well as its plasticity and regeneration—and represent a potential tool for neuro transplantation therapy and research. This study is focused on examination of the proliferation dynamic and fate of embryonic neural stem cells (eNSCs) under differentiating conditions. In this work, we analyzed eNSCs differentiating alone and in the presence of sonic hedgehog (SHH) or triiodothyronine (T3) which play an important role in the development of the CNS. We found that inhibition of the SHH pathway and activation of the T3 pathway increased cellular health and survival of differentiating eNSCs. In addition, T3 was able to increase the expression of the gene for the receptor smoothened (Smo), which is part of the SHH signaling cascade, while SHH increased the expression of the T3 receptor beta gene (Thrb). This might be the reason why the combination of SHH and T3 increased the expression of the thyroxine 5-deiodinase type III gene (Dio3), which inhibits T3 activity, which in turn affects cellular health and proliferation activity of eNSCs.

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Sonic Hedgehog modulates the inflammatory response and improves functional recovery after spinal cord injury in a thoracic contusion–compression model

European Spine Journal ◽

10.1007/s00586-021-06796-2 ◽

2021 ◽

Author(s):

Hao Zhang ◽

Alexander Younsi ◽

Guoli Zheng ◽

Mohamed Tail ◽

Anna-Kathrin Harms ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Sonic Hedgehog ◽

Functional Recovery ◽

Intrathecal Administration ◽

Neuroprotective Effects ◽

Thoracic Spinal Cord ◽

Shh Pathway ◽

Thoracic Spinal ◽

Cord Injury

Abstract Purpose The Sonic Hedgehog (Shh) pathway has been associated with a protective role after injury to the central nervous system (CNS). We, therefore, investigated the effects of intrathecal Shh-administration in the subacute phase after thoracic spinal cord injury (SCI) on secondary injury processes in rats. Methods Twenty-one Wistar rats were subjected to thoracic clip-contusion/compression SCI at T9. Animals were randomized into three treatment groups (Shh, Vehicle, Sham). Seven days after SCI, osmotic pumps were implanted for seven-day continuous intrathecal administration of Shh. Basso, Beattie and Bresnahan (BBB) score, Gridwalk test and bodyweight were weekly assessed. Animals were sacrificed six weeks after SCI and immunohistological analyses were conducted. The results were compared between groups and statistical analysis was performed (p < 0.05 was considered significant). Results The intrathecal administration of Shh led to significantly increased polarization of macrophages toward the anti-inflammatory M2-phenotype, significantly decreased T-lymphocytic invasion and significantly reduced resident microglia six weeks after the injury. Reactive astrogliosis was also significantly reduced while changes in size of the posttraumatic cyst as well as the overall macrophagic infiltration, although reduced, remained insignificant. Finally, with the administration of Shh, gain of bodyweight (216.6 ± 3.65 g vs. 230.4 ± 5.477 g; p = 0.0111) and BBB score (8.2 ± 0.2 vs. 5.9 ± 0.7 points; p = 0.0365) were significantly improved compared to untreated animals six weeks after SCI as well. Conclusion Intrathecal Shh-administration showed neuroprotective effects with attenuated neuroinflammation, reduced astrogliosis and improved functional recovery six weeks after severe contusion/compression SCI.

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