The transcription factor STAT2 enhances proteasomal degradation of RCAN1 through the ubiquitin E3 ligase FBW7

Jee Won Lee; Hye Seon Kang; Jae Youn Lee; Eun Jung Lee; Hyewhon Rhim; Joo Heon Yoon; Su Ryeon Seo; Kwang Chul Chung

doi:10.1016/j.bbrc.2012.03.007

The transcription factor STAT2 enhances proteasomal degradation of RCAN1 through the ubiquitin E3 ligase FBW7

Jee Won Lee, Hye Seon Kang, Jae Youn Lee, Eun Jung Lee, Hyewhon Rhim, Joo Heon Yoon, Su Ryeon Seo, Kwang Chul Chung

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

Down syndrome is the most common genetic disorder and is characterized by three copies of chromosome 21. Regulator of calcineurin 1 (RCAN1) is located close to the Down syndrome critical region (distal part of chromosome 21), and its product functions as an endogenous inhibitor of calcineurin signaling. RCAN1 protein stability is regulated by several inflammatory signaling factors, though the underlying mechanisms remain incompletely understood. Here, we report that RCAN1 interacts with the inflammation-linked transcription factor, signal transducer and activator of transcription 2 (STAT2) in mammalian cells. STAT2 overexpression decreased levels of RCAN1 protein. Decreases in RCAN1 were blocked by a proteasome inhibitor, indicating that STAT2 regulates RCAN1 degradation via the ubiquitin-proteasome system. Co-immunoprecipitation/immunoblot analyses showed that STAT2 enhanced RCAN1 ubiquitination through the ubiquitin E3 ligase FBW7. This pathway appeared to be physiologically relevant, as treatment of cells with interferon-α reduced RCAN1 levels through the activation of STAT2 and FBW7. Together, these results suggest that STAT2 influences diverse cellular processes linked to RCAN1 by negatively affecting RCAN1 protein stability.

Original language	English
Pages (from-to)	404-410
Number of pages	7
Journal	Biochemical and Biophysical Research Communications
Volume	420
Issue number	2
DOIs	https://doi.org/10.1016/j.bbrc.2012.03.007
Publication status	Published - 2012 Apr 6

Bibliographical note

Funding Information:
This study was supported by grants from the Korea Healthcare technology R&D Project (A092004 and A111653 to K.C.C.) funded by Ministry for Health, Welfare & Family Affairs, Republic of Korea. This work was also partially supported by grants from the Brain Research Center of the 21st Century Frontier Research Program Technology (2009K-001251 to K.C.C.), the National Research Foundation of Korea (NRF) (2010-0018916 to K.C.C.), and the Basic Science Research Program through NRF (2012-0000810 to K.C.C.) all funded by the Ministry of Education, Science and Technology (MEST), Republic of Korea.

All Science Journal Classification (ASJC) codes

Biophysics
Biochemistry
Molecular Biology
Cell Biology

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10.1016/j.bbrc.2012.03.007

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title = "The transcription factor STAT2 enhances proteasomal degradation of RCAN1 through the ubiquitin E3 ligase FBW7",

abstract = "Down syndrome is the most common genetic disorder and is characterized by three copies of chromosome 21. Regulator of calcineurin 1 (RCAN1) is located close to the Down syndrome critical region (distal part of chromosome 21), and its product functions as an endogenous inhibitor of calcineurin signaling. RCAN1 protein stability is regulated by several inflammatory signaling factors, though the underlying mechanisms remain incompletely understood. Here, we report that RCAN1 interacts with the inflammation-linked transcription factor, signal transducer and activator of transcription 2 (STAT2) in mammalian cells. STAT2 overexpression decreased levels of RCAN1 protein. Decreases in RCAN1 were blocked by a proteasome inhibitor, indicating that STAT2 regulates RCAN1 degradation via the ubiquitin-proteasome system. Co-immunoprecipitation/immunoblot analyses showed that STAT2 enhanced RCAN1 ubiquitination through the ubiquitin E3 ligase FBW7. This pathway appeared to be physiologically relevant, as treatment of cells with interferon-α reduced RCAN1 levels through the activation of STAT2 and FBW7. Together, these results suggest that STAT2 influences diverse cellular processes linked to RCAN1 by negatively affecting RCAN1 protein stability.",

author = "Lee, {Jee Won} and Kang, {Hye Seon} and Lee, {Jae Youn} and Lee, {Eun Jung} and Hyewhon Rhim and Yoon, {Joo Heon} and Seo, {Su Ryeon} and Chung, {Kwang Chul}",

note = "Funding Information: This study was supported by grants from the Korea Healthcare technology R&D Project (A092004 and A111653 to K.C.C.) funded by Ministry for Health, Welfare & Family Affairs, Republic of Korea. This work was also partially supported by grants from the Brain Research Center of the 21st Century Frontier Research Program Technology (2009K-001251 to K.C.C.), the National Research Foundation of Korea (NRF) (2010-0018916 to K.C.C.), and the Basic Science Research Program through NRF (2012-0000810 to K.C.C.) all funded by the Ministry of Education, Science and Technology (MEST), Republic of Korea.",

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AU - Lee, Jee Won

AU - Kang, Hye Seon

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AU - Lee, Eun Jung

AU - Rhim, Hyewhon

AU - Yoon, Joo Heon

AU - Seo, Su Ryeon

AU - Chung, Kwang Chul

N1 - Funding Information: This study was supported by grants from the Korea Healthcare technology R&D Project (A092004 and A111653 to K.C.C.) funded by Ministry for Health, Welfare & Family Affairs, Republic of Korea. This work was also partially supported by grants from the Brain Research Center of the 21st Century Frontier Research Program Technology (2009K-001251 to K.C.C.), the National Research Foundation of Korea (NRF) (2010-0018916 to K.C.C.), and the Basic Science Research Program through NRF (2012-0000810 to K.C.C.) all funded by the Ministry of Education, Science and Technology (MEST), Republic of Korea.

PY - 2012/4/6

Y1 - 2012/4/6

N2 - Down syndrome is the most common genetic disorder and is characterized by three copies of chromosome 21. Regulator of calcineurin 1 (RCAN1) is located close to the Down syndrome critical region (distal part of chromosome 21), and its product functions as an endogenous inhibitor of calcineurin signaling. RCAN1 protein stability is regulated by several inflammatory signaling factors, though the underlying mechanisms remain incompletely understood. Here, we report that RCAN1 interacts with the inflammation-linked transcription factor, signal transducer and activator of transcription 2 (STAT2) in mammalian cells. STAT2 overexpression decreased levels of RCAN1 protein. Decreases in RCAN1 were blocked by a proteasome inhibitor, indicating that STAT2 regulates RCAN1 degradation via the ubiquitin-proteasome system. Co-immunoprecipitation/immunoblot analyses showed that STAT2 enhanced RCAN1 ubiquitination through the ubiquitin E3 ligase FBW7. This pathway appeared to be physiologically relevant, as treatment of cells with interferon-α reduced RCAN1 levels through the activation of STAT2 and FBW7. Together, these results suggest that STAT2 influences diverse cellular processes linked to RCAN1 by negatively affecting RCAN1 protein stability.

AB - Down syndrome is the most common genetic disorder and is characterized by three copies of chromosome 21. Regulator of calcineurin 1 (RCAN1) is located close to the Down syndrome critical region (distal part of chromosome 21), and its product functions as an endogenous inhibitor of calcineurin signaling. RCAN1 protein stability is regulated by several inflammatory signaling factors, though the underlying mechanisms remain incompletely understood. Here, we report that RCAN1 interacts with the inflammation-linked transcription factor, signal transducer and activator of transcription 2 (STAT2) in mammalian cells. STAT2 overexpression decreased levels of RCAN1 protein. Decreases in RCAN1 were blocked by a proteasome inhibitor, indicating that STAT2 regulates RCAN1 degradation via the ubiquitin-proteasome system. Co-immunoprecipitation/immunoblot analyses showed that STAT2 enhanced RCAN1 ubiquitination through the ubiquitin E3 ligase FBW7. This pathway appeared to be physiologically relevant, as treatment of cells with interferon-α reduced RCAN1 levels through the activation of STAT2 and FBW7. Together, these results suggest that STAT2 influences diverse cellular processes linked to RCAN1 by negatively affecting RCAN1 protein stability.

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The transcription factor STAT2 enhances proteasomal degradation of RCAN1 through the ubiquitin E3 ligase FBW7

Abstract

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