更新于：2024-11-01

GLI1 x GLI2

更新于：2024-11-01

基本信息

关联

项与 GLI1 x GLI2 相关的药物

JC19

靶点

GLI1 x GLI2

作用机制

GLI1抑制剂 [+1]

在研机构

Alfasigma SpA

原研机构

Alfasigma SpA

在研适应症

黑色素瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

GANT61

靶点

GLI1 x GLI2

作用机制

GLI1抑制剂 [+1]

在研机构

Health Sciences University of Hokkaido

原研机构

Health Sciences University of Hokkaido

在研适应症

黑色素瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 GLI1 x GLI2 相关的临床结果

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100 项与 GLI1 x GLI2 相关的转化医学

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0 项与 GLI1 x GLI2 相关的专利（医药）

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684

项与 GLI1 x GLI2 相关的文献（医药）

2024-12-01·Cellular and Molecular Life Sciences

Mirk/Dyrk1B controls ventral spinal cord development via Shh pathway

Article

作者: Kokkorakis, N ; Politis, P K ; Matsas, R ; Douka, K ; Zagoraiou, L ; Gaitanou, M ; Nalmpanti, A

AbstractCross-talk between Mirk/Dyrk1B kinase and Sonic hedgehog (Shh)/Gli pathway affects physiology and pathology. Here, we reveal a novel role for Dyrk1B in regulating ventral progenitor and neuron subtypes in the embryonic chick spinal cord (SC) via the Shh pathway. Using in ovo gain-and-loss-of-function approaches at E2, we report that Dyrk1B affects the proliferation and differentiation of neuronal progenitors at E4 and impacts on apoptosis specifically in the motor neuron (MN) domain. Especially, Dyrk1B overexpression decreases the numbers of ventral progenitors, MNs, and V2a interneurons, while the pharmacological inhibition of endogenous Dyrk1B kinase activity by AZ191 administration increases the numbers of ventral progenitors and MNs. Mechanistically, Dyrk1B overexpression suppresses Shh, Gli2 and Gli3 mRNA levels, while conversely, Shh, Gli2 and Gli3 transcription is increased in the presence of Dyrk1B inhibitor AZ191 or Smoothened agonist SAG. Most importantly, in phenotype rescue experiments, SAG restores the Dyrk1B-mediated dysregulation of ventral progenitors. Further at E6, Dyrk1B affects selectively the medial lateral motor neuron column (LMCm), consistent with the expression of Shh in this region. Collectively, these observations reveal a novel regulatory function of Dyrk1B kinase in suppressing the Shh/Gli pathway and thus affecting ventral subtypes in the developing spinal cord. These data render Dyrk1B a possible therapeutic target for motor neuron diseases.

2024-11-01·Developmental Biology

CPLANE protein INTU regulates growth and patterning of the mouse lungs through cilia-dependent Hh signaling

Article

作者: Albert, Istvan ; Sebastian, Aswathy ; Ali, Shimaa ; Zeng, Huiqing ; Ramos-Medero, Adriana Sophia ; Dean, Charlotte ; Liu, Aimin

Congenital lung malformations are fatal at birth in their severe forms. Prevention and early intervention of these birth defects require a comprehensive understanding of the molecular mechanisms of lung development. We find that the loss of inturned (Intu), a cilia and planar polarity effector gene, severely disrupts growth and branching morphogenesis of the mouse embryonic lungs. Consistent with our previous results indicating an important role for Intu in ciliogenesis and hedgehog (Hh) signaling, we find greatly reduced number of primary cilia in both the epithelial and mesenchymal tissues of the lungs. We also find significantly reduced expression of Gli1 and Ptch1, direct targets of Hh signaling, suggesting disruption of cilia-dependent Hh signaling in Intu mutant lungs. An agonist of the Hh pathway activator, smoothened, increases Hh target gene expression and tubulogenesis in explanted wild type, but not Intu mutant, lungs, suggesting impaired Hh signaling response underlying lung morphogenetic defects in Intu mutants. Furthermore, removing both Gli2 and Intu completely abolishes branching morphogenesis of the lung, strongly supporting a mechanism by which Intu regulates lung growth and patterning through cilia-dependent Hh signaling. Moreover, a transcriptomics analysis identifies around 200 differentially expressed genes (DEGs) in Intu mutant lungs, including known Hh target genes Gli1, Ptch1/2 and Hhip. Genes involved in muscle differentiation and function are highly enriched among the DEGs, consistent with an important role of Hh signaling in airway smooth muscle differentiation. In addition, we find that the difference in gene expression between the left and right lungs diminishes in Intu mutants, suggesting an important role of Intu in asymmetrical growth and patterning of the mouse lungs.

2024-11-01·Life Science Alliance

mTORC1 hampers Hedgehog signaling inTsc2deficient cells

Article

作者: Østergaard, Elsebet ; Larsen, Lasse Jonsgaard ; Møller, Lisbeth Birk

The mTORC1-complex is negatively regulated by TSC1 and TSC2. Activation of Hedgehog signaling is strictly dependent on communication between Smoothened and the Hedgehog-signaling effector and transcription factor, GLI2, in the primary cilium. Details about this communication are not known, and we wanted to explore this further. Here we report that inTsc2−/−MEFs constitutively activated mTORC1 led to mis-localization of Smoothened to the plasma membrane, combined with increased concentration of GLI2 in the cilia and reduced Hedgehog signaling, measured by reduced expression of the Hedgehog target gene,Gli1. Inhibition of mTORC1 rescued the cellular localization of Smoothened to the cilia, reduced the cilia concentration of GLI2, and restored Hedgehog signaling. Our results reveal evidence for a two-step activation process of GLI2. The first step includes GLI2 stabilization and cilium localization, whereas the second step includes communication with cilia-localized Smoothened. We found that mTORC1 inhibits the second step. This is the first demonstration that mTORC1 is involved in the regulation of Hedgehog signaling.

项与 GLI1 x GLI2 相关的新闻（医药）

2024-02-06

·生物探索

Nat Commun | 浙江大学王继荣/吴希美等合作发现SHH信号在髓母细胞瘤中起重要作用

引言Sonic Hedgehog（SHH）信号转导及其效应转录因子GLI1的异常激活在SHH依赖性髓母细胞瘤(MBSHH)和基底细胞癌(BCC)的发生中至关重要。2024年2月2日，浙江大学王继荣、吴希美及浙大城市学院曾玲晖共同通讯在Nature Communications (IF 16.6)发表题为“Phosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma”的研究论文，该研究发现SHH以Smoothened依赖性方式使p38α（MAPK14）失活，相反，p38α直接在Ser937/Ser941上磷酸化GLI1(人/小鼠)，从而诱导GLI1的蛋白酶体降解，并否定SHH信号的转录。Gli1S941E系列功能丧失敲入显著降低平滑M2转基因诱导的自发性MBSHH的发生率和严重程度，而Gli1S941A功能获得性敲入表型Gli1转基因在皮肤中引起BCC样增殖。相应地，磷酸化Ser937-GLI1（GLI1的一种不稳定形式）与MBSHH患儿的总生存率呈正相关。总之，这些发现表明SHH诱导的p38α失活和随后的GLI1 去磷酸化和稳定在控制SHH信号传导方面的作用，并可能为未来干预MBSHH和BCC提供途径。Hedgehog (HH)信号通路对胚胎发育和肿瘤发生至关重要。哺乳动物HH配体由Sonic Hedgehog（SHH）、Indian Hedgehog（IHH）和Desert Hedgehog（DHH）组成。通过将HH配体与patched受体(PTCH)结合，可以解除对HH通路的辅助受体smoothened (SMO)的抑制，进而允许胶质瘤相关癌基因(GLI)家族转录因子GLI1、GLI2和GLI3诱导靶基因的转录。GLI2 和 GLI3 转录因子以蛋白酶体依赖性方式加工以产生转录激活因子或阻遏因子，而GLI1不仅是转录因子，也是HH信号通路的靶蛋白，通常被认为是转录激活因子，不需要蛋白酶体依赖的加工。融合抑制因子(SUFU)是一种细胞质蛋白，与所有三种GLI蛋白相互作用，并作为GLI转录因子的抑制因子。髓母细胞瘤（MB）是儿童最常见的小脑恶性肿瘤之一，约占所有儿童脑肿瘤的20%。MB有四个分子亚型，包括WNT组、SHH组、3组和4组，其中MBSHH是最常见的形式。基底细胞癌（BCC）是最常见的皮肤癌形式，也是所有癌症中最常见的形式。HH相关的基因改变常发生于MBSHH(87%)和BCC (85%), Ptch1和Sufu的功能缺失突变以及Smo和Gli2的功能获得性突变通常见于MBSHH和BCC，所有这些突变均导致GLI1水平上调。因此，GLI1被认为是这两种癌症发病率和严重程度的关键效应因素。在单倍不足的Ptch1+/-小鼠中，消融Gli1显著减少了MBSHH的自发形成。主要由于SHH信号通路的重要性，SMO抑制剂vismodegib和sonidegib已被批准用于治疗BCC，并正在进行MBSHH药物治疗的临床试验。尽管vismodegib对携带Ptch1或Smo突变的MBSHH有效力和疗效，但对于产生代偿机制并将SHH信号恢复至受体后水平的MBSHH无效，而且对Sufu或Gli基因改变的MBSHH几乎无影响。因此，在受体后水平，特别是在GLI1水平，识别出能够阻断信号传导的方法和分子，可能是这些疾病治疗干预的更好选择。SHH信号的激活使p38失活以诱导Gli1蛋白（Credit: Nature Communications）该研究证明了SHH通过使p38α失活来使hGLI1在Ser937上去磷酸化(mGli1在Ser941上)，从而稳定GLI1来诱导SHH信号的转录输出。因此，Gli1S941E的功能丧失性突变降低了SMO诱导的组成型活性MBSHH的发生率和严重程度，而Gli1S941A的功能获得性突变表型复制了Gli1转基因，导致皮肤BCC样增殖。重要的是，p-Ser937-GLI1水平与MBSHH患者的总生存期呈正相关。p38α介导的GLI1 Ser937/Ser941位点的磷酸化与MBSHH和BCC的发病和严重程度密切相关，因此干预GLI1的这一关键磷酸化位点可能为这些疾病的药物治疗提供新的途径。原文链接https://doi.org/10.1038/s41467-024-45315-x责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

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