Control of Murine Kidney Development by Sonic Hedgehog and its GLI Effectors

Gill, Paul; Rosenblum, Norman D.

doi:10.4161/cc.5.13.2928

Cited by 60 publications

(47 citation statements)

References 39 publications

(42 reference statements)

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“…As a morphogen, Shh is important in tissue patterning during embryonic development by controlling multiple biological processes including cell fate determination, cell proliferation and differentiation (Gill and Rosenblum, 2006; Pan et al, 2013). Human Shh is synthesized as a 45 kD precursor protein with 462 amino acids, in which the first 23 amino acids serves as a signal peptide.…”

Section: Sonic Hedgehog Signaling: Components Routes and Mechanismmentioning

confidence: 99%

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Zhou

Tan

Liu

2016

Sci. China Life Sci.

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The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedgehog ligands, sonic hedgehog (Shh) is known to be associated with kidney development and tissue repair after various insults. Recent studies uncover an intrinsic link between dysregulated Shh signaling and renal fibrogenesis. In various types of chronic kidney disease (CKD), Shh is upregulated specifically in renal tubular epithelium but targets interstitial fibroblasts, thereby mediating a dynamic epithelial-mesenchymal communication (EMC). Tubule-derived Shh acts as a growth factor for interstitial fibroblasts and controls a hierarchy of fibrosis-related genes, which lead to the excessive deposition of extracellular matrix in renal interstitium. In this review, we recapitulate the principle of Shh signaling, its activation and regulation in a variety of kidney diseases. We also discuss the potential mechanisms by which Shh promotes renal fibrosis and assess the efficacy of blocking this signaling in preclinical settings. Continuing these lines of investigations will provide novel opportunities for designing effective therapies to improve CKD prognosis in patients.

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Section: Sonic Hedgehog Signaling: Components Routes and Mechanismmentioning

confidence: 99%

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Zhou

Tan

Liu

2016

Sci. China Life Sci.

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“…35 One such event appears to be generating activator forms of GLI Zn-finger transcription factors to turn on downstream genes. [34][35][36][37][38] In NIH3T3 cells, a constitutively active form of SMO activates the HH pathway regardless of Gas1 over-expression or Gas1 RNAi. 30 Conversely, a constitutively active form of PTC1 that cannot bind HH represses HH pathway activation but such repression can be overcome by Gas1 overexpression plus SHH application, presumably by acting through the endogenous wild type PTC1 and titrating away the effects of the mutant PTC1.…”

Section: Discovery Of a Gas1 Ligandmentioning

confidence: 99%

The Role of Gas1 in Embryonic Development and its Implications for Human Disease

Martinelli¹,

Fan²

2007

Cell Cycle

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Growth arrest specific gene 1 (Gas1) has long been regarded as a cell cycle inhibitor of the G 0 to S phase transition. How GAS1, a GPI-anchored plasma membrane protein, directs intracellular changes without an extracellular ligand or a transmembrane protein partner has been puzzling. A recent series of biochemical and molecular genetic studies assigned the mammalian Hedgehog (HH) growth factor to be a ligand for GAS1 in vitro and in vivo. HH has enjoyed considerable attention for its profound role in embryonic patterning as a classic morphogen, i.e. inducing various cell types in a concentrationdependent manner. GAS1 appears to help transform the HH concentration gradient into its morphogenic activity gradient by acting cooperatively with the HH receptor, the 12-transmembrane protein Patched 1 (PTC1). These findings provoke intriguing thoughts on how HH and GAS1 may coordinate cell proliferation and differentiation to create biological patterns. The role of HH extends to human genetic diseases, stem cell renewal, and cancer growth, and we consider the possibility of GAS1's involvement in these processes as well.Precise integration between cell proliferation and cell type specification during embryogenesis directs the formation and function of each tissue. Integration between these two programs in a given cell is largely determined by intercellular signaling molecules. Here, we review the recent 'unlikely marriage' between two extracellular molecules, GAS1 and HH, and the implications on coordinated cell proliferation and cell type specification. Gas1 the cell cycle InhIbItorIn 1988, Gas1 was identified as one of six genes that were transcriptionally up-regulated in NIH3T3 cells arrested in cell cycle upon serum starvation, a presumed G 0 arrest. 1 Among the six initially identified growth arrest specific (hence Gas) genes, only Gas1 could suppress cell cycle progression when overexpressed in non-transformed and certain oncogene-transformed NIH3T3 cells. [2][3][4] Because GAS1 overexpressing cells did not incorporate BrdU, it was thought that GAS1 blocked the G 0 to S phase transition. Deletion analysis of GAS1, an outer plasma membrane glycosylphosphatidylinositol (GPI)-linked protein of 37 kDa, concluded that it could induce growth arrest without its GPI anchor, suggesting that it acts through another membrane partner. 5,6 Interestingly, GAS1-induced growth arrest depended on the tumor suppressor gene p53. 7,8 Furthermore, c-Myc and v-Src, powerful proliferation promoting factors, repressed Gas1 expression, suggesting that Gas1 downregulation is an associated step in the promotion of proliferation. 9,10 By contrast, senescent fibroblast cells, though cease proliferating, do not express Gas1. 11 These studies together suggest that GAS1 is a negative cell growth regulator rather than a senescence mediator. However, evidence to demonstrate such a function for Gas1 in an animal model is lacking.

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“…Gli1 is upregulated in the majority of pancreatic cancer tissues and its level of expression is positively correlated with Hh signaling (47). Cyclin D1, another Gli target gene, functions as a cell cycle regulator and is important in carcinogenesis (48,49). In the present study, basal levels of Gli1 and cyclin D1 were elevated in PANC-1 and AsPC-1 cells.…”

Section: Concentration Of Gsl µM -----------------------------------mentioning

confidence: 48%

A sesquiterpene lactone from Siegesbeckia glabrescens suppresses Hedgehog/Gli-mediated transcription in pancreatic cancer cells

Lee

et al. 2016

Oncology Letters

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Abstract. Pancreatic cancer is aggressive and therefore difficult to treat; however, continued efforts have been made with the aim of developing an effective therapy against the disease. The Hedgehog (Hh) signaling pathway is reportedly involved in the proliferation and survival of pancreatic cancer cells. The transcription factor glioma-associated oncogene (Gli) is a key component of the Hh signaling pathway and the primary effector of pancreatic cancer development. Inhibiting Gli is a proven therapeutic strategy for this disease. The present study examined the regulation of Gli and the expression of its target genes to identify an inhibitor of the Sonic Hh (Shh) pathway. A germacranolide sesquiterpene lactone (GSL) was isolated from Siegesbeckia glabrescens as an inhibitor of Gli-mediated transcription. The results demonstrated that GSL inhibited Shh-induced osteoblast differentiation and Gli homolog 1 (Gli1)-mediated transcriptional activity in mesenchymal C3H10T1/2 stem cells. Furthermore, GSL suppressed Gli-mediated transcriptional activity in human pancreatic cancer PANC-1 and AsPC-1 cells, which resulted in reduced cancer cell proliferation and downregulated expression of the Gli-target genes, Gli1 and cyclin D1. A sesquiterpene lactone from S. glabrescens may therefore serve as a candidate for the treatment of Hh/Gli-dependent pancreatic cancer.

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Control of Murine Kidney Development by Sonic Hedgehog and its GLI Effectors

Cited by 60 publications

References 39 publications

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Sonic hedgehog signaling in kidney fibrosis: a master communicator

The Role of Gas1 in Embryonic Development and its Implications for Human Disease

A sesquiterpene lactone from Siegesbeckia glabrescens suppresses Hedgehog/Gli-mediated transcription in pancreatic cancer cells

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