DeSUMOylation of Gli1 by SENP1 Attenuates Sonic Hedgehog Signaling

Liu, Huaize; Yan, Sen; Ding, Jie; Yu, Tingting; Cheng, Steven Y.

doi:10.1128/mcb.00579-16

Cited by 11 publications

(12 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pias1 small ubiquitin-related modifier (SUMO) ligase was found to decrease GLI1 ubiquitination, thereby increasing GLI1 transcriptional activity in vitro [117]. Alternatively, the sentrin-specific peptidase (SENP1) is the specific deSUMOylation enzyme for GLI1 that stabilizes GLI1 through competition for conserved lysine residues [118]. Furthermore, acetylation of GLI1 at lysine residue K518 by the acetyltransferase p300/CBP reduces the transcriptional activity of GLI1 through sequestering inactive GLI1, inhibition of DNA binding, and increasing nuclear export [105,119].…”

Section: Type Iii-mechanisms Independent Of Upstream Ptch1-smo Signalingmentioning

confidence: 99%

Hedgehog Signaling and Truncated GLI1 in Cancer

Doheny

Manore

Wong

et al. 2020

Cells

128

View full text Add to dashboard Cite

The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.

show abstract

Section: Type Iii-mechanisms Independent Of Upstream Ptch1-smo Signalingmentioning

confidence: 99%

Hedgehog Signaling and Truncated GLI1 in Cancer

Doheny

Manore

Wong

et al. 2020

Cells

128

View full text Add to dashboard Cite

show abstract

“…Sentrin-specific peptidase (SENP1) was shown to specifically desumoylate Gli1 and negatively regulate Hh signaling. SENP1-mediated desumoylation promotes Gli1 ubiquitination and facilitates Gli1 nuclear export [70].…”

Section: Regulation Of Gli Proteins By Posttranslational Modificatmentioning

confidence: 99%

Gli Proteins: Regulation in Development and Cancer

Niewiadomski

Niedziółka

Markiewicz

et al. 2019

Cells

141

124

View full text Add to dashboard Cite

Gli proteins are transcriptional effectors of the Hedgehog signaling pathway. They play key roles in the development of many organs and tissues, and are deregulated in birth defects and cancer. We review the molecular mechanisms of Gli protein regulation in mammals, with special emphasis on posttranslational modifications and intracellular transport. We also discuss how Gli proteins interact with co-activators and co-repressors to fine-tune the expression of Hedgehog target genes. Finally, we provide an overview of the regulation of developmental processes and tissue regeneration by Gli proteins and discuss how these proteins are involved in cancer progression, both through canonical regulation via the Hedgehog pathway and through cross-talk with other signaling pathways.

show abstract

“…GLI transcription factors are finely regulated at the post-translational level by various modifications, such as phosphorylation (7), ubiquitination (8), acetylation (9,10) and SUMOylation (11). It has previously been demonstrated that targeting some of these GLI modifications may prove to be an additional avenue with which to inhibit HH-regulated transcriptional output (12).…”

Section: Introductionmentioning

confidence: 99%

Mitogen-activated kinase kinase kinase 1 inhibits hedgehog signaling and medulloblastoma growth through GLI1 phosphorylation

et al. 2018

View full text Add to dashboard Cite

The aberrant activation of hedgehog (HH) signaling is a leading cause of the development of medulloblastoma, a pediatric tumor of the cerebellum. The FDA-approved HH inhibitor, Vismodegib, which targets the transmembrane transducer SMO, has shown limited efficacy in patients with medulloblastoma, due to compensatory mechanisms that maintain an active HH-GLI signaling status. Thus, the identification of novel actionable mechanisms, directly affecting the activity of the HH-regulated GLI transcription factors is an important goal for these malignancies. In this study, using gene expression and reporter assays, combined with biochemical and cellular analyses, we demonstrate that mitogen-activated kinase kinase kinase 1 (MEKK1), the most upstream kinase of the mitogen-activated protein kinase (MAPK) phosphorylation modules, suppresses HH signaling by associating and phosphorylating GLI1, the most potent HH-regulated transcription factor. Phosphorylation occurred at multiple residues in the C-terminal region of GLI1 and was followed by an increased association with the cytoplasmic proteins 14-3-3. Of note, the enforced expression of MEKK1 or the exposure of medulloblastoma cells to the MEKK1 activator, Nocodazole, resulted in a marked inhibitory effect on GLI1 activity and tumor cell proliferation and viability. Taken together, the results of this study shed light on a novel regulatory mechanism of HH signaling, with potentially relevant implications in cancer therapy.

show abstract

DeSUMOylation of Gli1 by SENP1 Attenuates Sonic Hedgehog Signaling

Cited by 11 publications

References 52 publications

Hedgehog Signaling and Truncated GLI1 in Cancer

Hedgehog Signaling and Truncated GLI1 in Cancer

Gli Proteins: Regulation in Development and Cancer

Mitogen-activated kinase kinase kinase 1 inhibits hedgehog signaling and medulloblastoma growth through GLI1 phosphorylation

Contact Info

Product

Resources

About