SENP1-mediated deSUMOylation of USP28 regulated HIF-1α accumulation and activation during hypoxia response 06 Biological Sciences 0601 Biochemistry and Cell Biology

Shi Chun Du, Lan Zhu, Yu Xing Wang, Jie Liu, Die Zhang, Yu Lu Chen, Qing Peng, Wei Liu, Bin Liu

Research output: Contribution to journalArticle

Abstract

Background: The ubiquitin-specific protease 28 (USP28) is an oncogenic deubiquitinase, which plays a critical role in tumorigenesis via antagonizing the ubiquitination and degradation of tumor suppressor protein FBXW7-mediated oncogenic substrates. USP28 controls hypoxia-dependent angiogenesis and metastasis by preventing FBXW7-dependent hypoxia-inducible transcription factor-1α (HIF-1α) degradation during hypoxia. However, it remains unclear how USP28 activation and HIF-1α signaling are coordinated in response to hypoxia. Methods: The in vitro deubiquitinating activity assay was used to determine the regulation of USP28 by hypoxia. The co-immunoprecipitation and GST Pull-down assays were used to determine the interaction between USP28 and SENP1. The in vivo deSUMOylation assay was performed to determine the regulation of USP28 by SENP1. The luciferase reporter assay was used to determine the transcriptional activity of HIF-1α. Results: Here, we report that USP28 is a SUMOylated protein in normoxia with moderate deubiquitinating activity towards HIF-1α in vitro, while hypoxia and HIF-1α activate USP28 through SENP1-mediated USP28 deSUMOylation to further accumulate HIF-1α protein in cells. In agreement with this, a SUMOylation mutant USP28 showed enhanced ability to increase HIF-1α level as well as control the transcriptional activity of HIF-1α. Conclusion: Collectively, our results reveal a novel SENP1-USP28-HIF-1α positive feedback loop to maximize the concentration of HIF-1a protein and amplify its downstream effects during hypoxia response.

Original languageEnglish (US)
Article number4
JournalCancer Cell International
Volume19
Issue number1
DOIs
StatePublished - Jan 3 2019

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Ubiquitin-Specific Proteases
Hypoxia-Inducible Factor 1
Biological Science Disciplines
Biochemistry
Cell Biology
Transcription Factors
Hypoxia
Sumoylation
Tumor Suppressor Proteins
Proteins
Ubiquitination
Luciferases
Immunoprecipitation

Keywords

  • HIF-1α
  • Hypoxia
  • SENP1
  • USP28

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

SENP1-mediated deSUMOylation of USP28 regulated HIF-1α accumulation and activation during hypoxia response 06 Biological Sciences 0601 Biochemistry and Cell Biology. / Du, Shi Chun; Zhu, Lan; Wang, Yu Xing; Liu, Jie; Zhang, Die; Chen, Yu Lu; Peng, Qing; Liu, Wei; Liu, Bin.

In: Cancer Cell International, Vol. 19, No. 1, 4, 03.01.2019.

Research output: Contribution to journalArticle

Du, Shi Chun ; Zhu, Lan ; Wang, Yu Xing ; Liu, Jie ; Zhang, Die ; Chen, Yu Lu ; Peng, Qing ; Liu, Wei ; Liu, Bin. / SENP1-mediated deSUMOylation of USP28 regulated HIF-1α accumulation and activation during hypoxia response 06 Biological Sciences 0601 Biochemistry and Cell Biology. In: Cancer Cell International. 2019 ; Vol. 19, No. 1.
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abstract = "Background: The ubiquitin-specific protease 28 (USP28) is an oncogenic deubiquitinase, which plays a critical role in tumorigenesis via antagonizing the ubiquitination and degradation of tumor suppressor protein FBXW7-mediated oncogenic substrates. USP28 controls hypoxia-dependent angiogenesis and metastasis by preventing FBXW7-dependent hypoxia-inducible transcription factor-1α (HIF-1α) degradation during hypoxia. However, it remains unclear how USP28 activation and HIF-1α signaling are coordinated in response to hypoxia. Methods: The in vitro deubiquitinating activity assay was used to determine the regulation of USP28 by hypoxia. The co-immunoprecipitation and GST Pull-down assays were used to determine the interaction between USP28 and SENP1. The in vivo deSUMOylation assay was performed to determine the regulation of USP28 by SENP1. The luciferase reporter assay was used to determine the transcriptional activity of HIF-1α. Results: Here, we report that USP28 is a SUMOylated protein in normoxia with moderate deubiquitinating activity towards HIF-1α in vitro, while hypoxia and HIF-1α activate USP28 through SENP1-mediated USP28 deSUMOylation to further accumulate HIF-1α protein in cells. In agreement with this, a SUMOylation mutant USP28 showed enhanced ability to increase HIF-1α level as well as control the transcriptional activity of HIF-1α. Conclusion: Collectively, our results reveal a novel SENP1-USP28-HIF-1α positive feedback loop to maximize the concentration of HIF-1a protein and amplify its downstream effects during hypoxia response.",
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T1 - SENP1-mediated deSUMOylation of USP28 regulated HIF-1α accumulation and activation during hypoxia response 06 Biological Sciences 0601 Biochemistry and Cell Biology

AU - Du, Shi Chun

AU - Zhu, Lan

AU - Wang, Yu Xing

AU - Liu, Jie

AU - Zhang, Die

AU - Chen, Yu Lu

AU - Peng, Qing

AU - Liu, Wei

AU - Liu, Bin

PY - 2019/1/3

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N2 - Background: The ubiquitin-specific protease 28 (USP28) is an oncogenic deubiquitinase, which plays a critical role in tumorigenesis via antagonizing the ubiquitination and degradation of tumor suppressor protein FBXW7-mediated oncogenic substrates. USP28 controls hypoxia-dependent angiogenesis and metastasis by preventing FBXW7-dependent hypoxia-inducible transcription factor-1α (HIF-1α) degradation during hypoxia. However, it remains unclear how USP28 activation and HIF-1α signaling are coordinated in response to hypoxia. Methods: The in vitro deubiquitinating activity assay was used to determine the regulation of USP28 by hypoxia. The co-immunoprecipitation and GST Pull-down assays were used to determine the interaction between USP28 and SENP1. The in vivo deSUMOylation assay was performed to determine the regulation of USP28 by SENP1. The luciferase reporter assay was used to determine the transcriptional activity of HIF-1α. Results: Here, we report that USP28 is a SUMOylated protein in normoxia with moderate deubiquitinating activity towards HIF-1α in vitro, while hypoxia and HIF-1α activate USP28 through SENP1-mediated USP28 deSUMOylation to further accumulate HIF-1α protein in cells. In agreement with this, a SUMOylation mutant USP28 showed enhanced ability to increase HIF-1α level as well as control the transcriptional activity of HIF-1α. Conclusion: Collectively, our results reveal a novel SENP1-USP28-HIF-1α positive feedback loop to maximize the concentration of HIF-1a protein and amplify its downstream effects during hypoxia response.

AB - Background: The ubiquitin-specific protease 28 (USP28) is an oncogenic deubiquitinase, which plays a critical role in tumorigenesis via antagonizing the ubiquitination and degradation of tumor suppressor protein FBXW7-mediated oncogenic substrates. USP28 controls hypoxia-dependent angiogenesis and metastasis by preventing FBXW7-dependent hypoxia-inducible transcription factor-1α (HIF-1α) degradation during hypoxia. However, it remains unclear how USP28 activation and HIF-1α signaling are coordinated in response to hypoxia. Methods: The in vitro deubiquitinating activity assay was used to determine the regulation of USP28 by hypoxia. The co-immunoprecipitation and GST Pull-down assays were used to determine the interaction between USP28 and SENP1. The in vivo deSUMOylation assay was performed to determine the regulation of USP28 by SENP1. The luciferase reporter assay was used to determine the transcriptional activity of HIF-1α. Results: Here, we report that USP28 is a SUMOylated protein in normoxia with moderate deubiquitinating activity towards HIF-1α in vitro, while hypoxia and HIF-1α activate USP28 through SENP1-mediated USP28 deSUMOylation to further accumulate HIF-1α protein in cells. In agreement with this, a SUMOylation mutant USP28 showed enhanced ability to increase HIF-1α level as well as control the transcriptional activity of HIF-1α. Conclusion: Collectively, our results reveal a novel SENP1-USP28-HIF-1α positive feedback loop to maximize the concentration of HIF-1a protein and amplify its downstream effects during hypoxia response.

KW - HIF-1α

KW - Hypoxia

KW - SENP1

KW - USP28

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