Small Ubiquitin-like Modifier (SUMO) Modification Inhibits GLI2 Protein Transcriptional Activity in Vitro and in Vivo

Han, Lizhang; Pan, Yong; Wang, Baolin

doi:10.1074/jbc.m112.359299

Cited by 26 publications

(27 citation statements)

References 21 publications

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“…3A,B,E). Consistent with previous findings, Gli2-containing individual K.R substitutions displayed greater transcriptional activity than wild-type Gli2 and multiple mutations increased this hyperactivity (Han et al, 2012) (supplementary material Fig. S3E).…”

Section: Resultssupporting

confidence: 91%

“…Phosphorylation of the phosphorylation cluster promotes the degradation of Gli2 by SCF bTRCP/Slimb and enhances sumoylation, a post-translational modification that inhibits Gli2 transcriptional activity (Bhatia et al, 2006;Cox et al, 2010;Han et al, 2012;Pan et al, 2006). Two putative sumoylation sites flank each end of the zinc finger domain (Cox et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

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A central region of Gli2 regulates its localization to the primary cilium and transcriptional activity

Santos

Reiter

2014

Journal of Cell Science

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Signaling through vertebrate Hedgehog (Hh) proteins depends on the primary cilium. In response to Hh signals, the transcriptional activator of the pathway, Gli2, accumulates at the ciliary tip, raising the possibility that ciliary localization is important for Gli2 activation. To test this hypothesis, we used the Floxin system to create knockin Gli2 alleles in embryonic stem cells (ESCs) to allow methodical testing of which domains and residues are essential for the ciliary localization of Gli2. The Gli2 zinc fingers, transcriptional activation domain, repressor domain, phosphorylation cluster and a Sufu binding motif were each dispensable for ciliary localization. Mutating residues that are required for Gli2 sumoylation and nuclear trafficking also did not abrogate ciliary localization. By contrast, several other domains restricted Gli2 nuclear localization, and a central region, distinct from previously characterized domains, was required for ciliary localization. In addition to an inability to localize to cilia, Gli2 lacking this central domain was unable to activate target genes. Thus, our systematic analysis in ESCs reveals that distinct regions of Gli2 regulate its nuclear and ciliary localization. The identification of a domain essential for both ciliary localization and transcriptional activity suggests that ciliary localization of Gli2 is required for its activation.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

A central region of Gli2 regulates its localization to the primary cilium and transcriptional activity

Santos

Reiter

2014

Journal of Cell Science

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“…For instance, the level of Gli2 can be regulated by sumoylation, and PKA phosphorylation enhances Gli2 sumoylation, whereas Hh signaling inhibits it (32). Interestingly, we did not find that Pthlh in the absence of Sufu would regulate Gli2 levels, suggesting that this mechanism does not operate independently in growth plate chondrocytes.…”

Section: Discussioncontrasting

confidence: 61%

Suppressor of Fused (Sufu) Mediates the Effect of Parathyroid Hormone-like Hormone (Pthlh) on Chondrocyte Differentiation in the Growth Plate

Hsu¹,

Zhang²,

Cheng³

et al. 2012

Journal of Biological Chemistry

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Background: Hh and Pthlh signaling pathways play important roles in regulating growth plate chondrocyte differentiation. Results: Pthlh increases Sufu protein levels, and Sufu is required for the effect of Pthlh on chondrocyte differentiation. Conclusion: Pthlh regulates chondrocyte differentiation and Gli activity in a Sufu-dependent manner. Significance: The interaction between Pthlh, PKA, Sufu, and Gli transcriptional activities explains how Pthlh regulates chondrocyte differentiation.

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“…Actually, Gli proteins, the homologs of Ci in mammals, can be SUMOylated, as reported by two groups (Cox et al, 2010;Han et al, 2012), further supporting a conserved modification of the conserved transcription factors. However, their conclusions about the function of SUMOylation on Hh signaling activity are controversial.…”

Section: Sumo Conjugation Promotes CI Activity In Terms Of Cysc Prolisupporting

confidence: 52%

SUMO regulates somatic cyst stem cells maintenance and directly targets hedgehog pathway in adult Drosophila testis

Pan

Zhang

et al. 2016

Development

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SUMO (Small ubiquitin-related modifier) modification (SUMOylation) is a highly dynamic post-translational modification (PTM) that plays important roles in tissue development and disease progression. However, its function in adult stem cell maintenance is largely unknown. Here, we report the function of SUMOylation in somatic cyst stem cell (CySC) self-renewal in adult Drosophila testis. The SUMO pathway cell-autonomously regulates CySC maintenance. Reduction of SUMOylation promotes premature differentiation of CySCs and impedes the proliferation of CySCs, which leads to a reduction in the number of CySCs. Consistent with this, CySC clones carrying a mutation of the SUMO-conjugating enzyme are rapidly lost. Furthermore, inhibition of the SUMO pathway phenocopies disruption of the Hedgehog (Hh) pathway, and can block the proliferation of CySCs induced by Hh activation. Importantly, the SUMO pathway directly regulates the SUMOylation of Hh pathway transcription factor Cubitus interruptus (Ci), which is required for promoting CySC proliferation. Thus, we conclude that SUMO directly targets the Hh pathway and regulates CySC maintenance in adult Drosophila testis.

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Small Ubiquitin-like Modifier (SUMO) Modification Inhibits GLI2 Protein Transcriptional Activity in Vitro and in Vivo

Cited by 26 publications

References 21 publications

A central region of Gli2 regulates its localization to the primary cilium and transcriptional activity

A central region of Gli2 regulates its localization to the primary cilium and transcriptional activity

Suppressor of Fused (Sufu) Mediates the Effect of Parathyroid Hormone-like Hormone (Pthlh) on Chondrocyte Differentiation in the Growth Plate

SUMO regulates somatic cyst stem cells maintenance and directly targets hedgehog pathway in adult Drosophila testis

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