TRAF6 Restricts p53 Mitochondrial Translocation, Apoptosis, and Tumor Suppression

Xian Zhang; Chien Feng Li; Ling Zhang; Ching Yuan Wu; Lixia Han; Guoxiang Jin; Abdol Hossein Rezaeian; Fei Han; Chunfang Liu; Chuan Xu; Xiaohong Xu; Chih Yang Huang; Fuu Jen Tsai; Chang Hai Tsai; Kounosuke Watabe; Hui Kuan Lin

doi:10.1016/j.molcel.2016.10.002

TRAF6 Restricts p53 Mitochondrial Translocation, Apoptosis, and Tumor Suppression

Xian Zhang, Chien Feng Li, Ling Zhang, Ching Yuan Wu, Lixia Han, Guoxiang Jin, Abdol Hossein Rezaeian, Fei Han, Chunfang Liu, Chuan Xu, Xiaohong Xu, Chih Yang Huang, Fuu Jen Tsai, Chang Hai Tsai, Kounosuke Watabe, Hui Kuan Lin^*

^*Corresponding author for this work

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

67 Scopus citations

Abstract

Mitochondrial p53 is involved in apoptosis and tumor suppression. However, its regulation is not well studied. Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK. Genotoxic stress reduces this ubiquitination in cytosol by S13/T330 phosphorylation-dependent translocation of TRAF6 from cytosol to nucleus, where TRAF6 also facilitates the K63-linked ubiquitination of nuclear p53 and its transactivation by recruiting p300 for p53 acetylation. Functionally, K63-linked ubiquitination of p53 compromised p53-mediated apoptosis and tumor suppression. Colorectal cancer samples with WT p53 reveal that TRAF6 overexpression negatively correlates with apoptosis and predicts poor response to chemotherapy and radiotherapy. Together, our study identifies TRAF6 as a critical gatekeeper to restrict p53 mitochondrial translocation, and such mechanism may contribute to tumor development and drug resistance.

Original language	English
Pages (from-to)	803-814
Number of pages	12
Journal	Molecular Cell
Volume	64
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2016.10.002
State	Published - 17 11 2016
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.

Keywords

K63-linked ubiquitination of p53
MCL1/BaK
TRAF6 inhibits apoptosis
colorectal cancer
genotoxic stress
p300 recruitment
p53 K24 ubiquitination
p53 mitochondrial translocation
p53 transactivation
tumor suppression

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10.1016/j.molcel.2016.10.002

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title = "TRAF6 Restricts p53 Mitochondrial Translocation, Apoptosis, and Tumor Suppression",

abstract = "Mitochondrial p53 is involved in apoptosis and tumor suppression. However, its regulation is not well studied. Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK. Genotoxic stress reduces this ubiquitination in cytosol by S13/T330 phosphorylation-dependent translocation of TRAF6 from cytosol to nucleus, where TRAF6 also facilitates the K63-linked ubiquitination of nuclear p53 and its transactivation by recruiting p300 for p53 acetylation. Functionally, K63-linked ubiquitination of p53 compromised p53-mediated apoptosis and tumor suppression. Colorectal cancer samples with WT p53 reveal that TRAF6 overexpression negatively correlates with apoptosis and predicts poor response to chemotherapy and radiotherapy. Together, our study identifies TRAF6 as a critical gatekeeper to restrict p53 mitochondrial translocation, and such mechanism may contribute to tumor development and drug resistance.",

keywords = "K63-linked ubiquitination of p53, MCL1/BaK, TRAF6 inhibits apoptosis, colorectal cancer, genotoxic stress, p300 recruitment, p53 K24 ubiquitination, p53 mitochondrial translocation, p53 transactivation, tumor suppression",

author = "Xian Zhang and Li, {Chien Feng} and Ling Zhang and Wu, {Ching Yuan} and Lixia Han and Guoxiang Jin and Rezaeian, {Abdol Hossein} and Fei Han and Chunfang Liu and Chuan Xu and Xiaohong Xu and Huang, {Chih Yang} and Tsai, {Fuu Jen} and Tsai, {Chang Hai} and Kounosuke Watabe and Lin, {Hui Kuan}",

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year = "2016",

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doi = "10.1016/j.molcel.2016.10.002",

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T1 - TRAF6 Restricts p53 Mitochondrial Translocation, Apoptosis, and Tumor Suppression

AU - Zhang, Xian

AU - Li, Chien Feng

AU - Zhang, Ling

AU - Wu, Ching Yuan

AU - Han, Lixia

AU - Jin, Guoxiang

AU - Rezaeian, Abdol Hossein

AU - Han, Fei

AU - Liu, Chunfang

AU - Xu, Chuan

AU - Xu, Xiaohong

AU - Huang, Chih Yang

AU - Tsai, Fuu Jen

AU - Tsai, Chang Hai

AU - Watabe, Kounosuke

AU - Lin, Hui Kuan

PY - 2016/11/17

Y1 - 2016/11/17

N2 - Mitochondrial p53 is involved in apoptosis and tumor suppression. However, its regulation is not well studied. Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK. Genotoxic stress reduces this ubiquitination in cytosol by S13/T330 phosphorylation-dependent translocation of TRAF6 from cytosol to nucleus, where TRAF6 also facilitates the K63-linked ubiquitination of nuclear p53 and its transactivation by recruiting p300 for p53 acetylation. Functionally, K63-linked ubiquitination of p53 compromised p53-mediated apoptosis and tumor suppression. Colorectal cancer samples with WT p53 reveal that TRAF6 overexpression negatively correlates with apoptosis and predicts poor response to chemotherapy and radiotherapy. Together, our study identifies TRAF6 as a critical gatekeeper to restrict p53 mitochondrial translocation, and such mechanism may contribute to tumor development and drug resistance.

AB - Mitochondrial p53 is involved in apoptosis and tumor suppression. However, its regulation is not well studied. Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK. Genotoxic stress reduces this ubiquitination in cytosol by S13/T330 phosphorylation-dependent translocation of TRAF6 from cytosol to nucleus, where TRAF6 also facilitates the K63-linked ubiquitination of nuclear p53 and its transactivation by recruiting p300 for p53 acetylation. Functionally, K63-linked ubiquitination of p53 compromised p53-mediated apoptosis and tumor suppression. Colorectal cancer samples with WT p53 reveal that TRAF6 overexpression negatively correlates with apoptosis and predicts poor response to chemotherapy and radiotherapy. Together, our study identifies TRAF6 as a critical gatekeeper to restrict p53 mitochondrial translocation, and such mechanism may contribute to tumor development and drug resistance.

KW - K63-linked ubiquitination of p53

KW - MCL1/BaK

KW - TRAF6 inhibits apoptosis

KW - colorectal cancer

KW - genotoxic stress

KW - p300 recruitment

KW - p53 K24 ubiquitination

KW - p53 mitochondrial translocation

KW - p53 transactivation

KW - tumor suppression

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U2 - 10.1016/j.molcel.2016.10.002

DO - 10.1016/j.molcel.2016.10.002

M3 - 文章

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AN - SCOPUS:84995560687

SN - 1097-2765

VL - 64

SP - 803

EP - 814

JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -

TRAF6 Restricts p53 Mitochondrial Translocation, Apoptosis, and Tumor Suppression

Abstract

Bibliographical note

Keywords

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