Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin ligase 'Synoviolin'.
Synoviolin, also called HRD1, is an E3 ubiquitin ligase and is implicated in endoplasmic reticulum -associated degradation. In mammals, Synoviolin plays crucial roles in various physiological and pathological processes, including embryogenesis and the pathogenesis of arthropathy. However, little is known about the molecular mechanisms of Synoviolin in these actions. To clarify these issues, we analyzed the profile of protein expression in synoviolin-null cells. Here, we report that Synoviolin targets tumor suppressor gene p53 for ubiquitination. Synoviolin sequestrated and metabolized p53 in the cytoplasm and negatively regulated its cellular level and biological functions, including transcription, cell cycle regulation and apoptosis. Furthermore, these p53 regulatory functions of Synoviolin were irrelevant to other E3 ubiquitin ligases for p53, such as MDM2, Pirh2 and Cop1, which form autoregulatory feedback loops. Our results provide novel insights into p53 signaling mediated by Synoviolin.
Yamasaki
Satoshi
S
Department of Genome Science, Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, Japan.
Yagishita
Naoko
N
Sasaki
Takeshi
T
Nakazawa
Minako
M
Kato
Yukihiro
Y
Yamadera
Tadayuki
T
Bae
Eunkyung
E
Toriyama
Sayumi
S
Ikeda
Rie
R
Zhang
Lei
L
Fujitani
Kazuko
K
Yoo
Eunkyung
E
Tsuchimochi
Kaneyuki
K
Ohta
Tomohiko
T
Araya
Natsumi
N
Fujita
Hidetoshi
H
Aratani
Satoko
S
Eguchi
Katsumi
K
Komiya
Setsuro
S
Maruyama
Ikuro
I
Higashi
Nobuyo
N
Sato
Mitsuru
M
Senoo
Haruki
H
Ochi
Takahiro
T
Yokoyama
Shigeyuki
S
Amano
Tetsuya
T
Kim
Jaeseob
J
Gay
Steffen
S
Fukamizu
Akiyoshi
A
Nishioka
Kusuki
K
Tanaka
Keiji
K
Nakajima
Toshihiro
T
D000818:Animals; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D004331:Drosophila melanogaster; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D010957:Plasmids / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D015398:Signal Transduction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*; D025801:Ubiquitin / Q000737:chemistry; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D044763:Ubiquitin-Conjugating Enzymes; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex