SOCS1 [corrected] inhibits HPV-E7-mediated transformation by inducing degradation of E7 protein.
Human papilloma viruses (HPVs) are small double-stranded DNA viruses that infect mucosal and cutaneous epithelium and induce cervical cancer. It has been shown that interferon (IFN)gamma suppresses proliferation of HPV-infected cells by suppressing expression of HPV E7. Here, we found that IFNgamma induces not only suppression of E7 transcription but also proteasome-dependent degradation. Suppressor of cytokine signaling-1 (SOCS1)/JAB, a suppressor of cytokine signaling, is known to be induced by IFNgamma, and functions as an antioncogene against various hematopoietic oncogenic proteins. SOCS1 contains the SOCS-box, which is shown to recruit ubiquitin transferase to the molecules that interact with SOCS1. We found that SOCS1 interacted with HPV E7 protein and induced ubiquitination and degradation of E7 in a SOCS-box-dependent manner. SOCS1 overexpression also increased Rb protein levels and suppressed proliferation of cervical cancer cell lines infected with HPV. Moreover, E7 protein levels were higher and Rb protein levels were lower in SOCS1-deficient fibroblasts infected with retrovirus vector carrying E7 gene than in wild-type fibroblasts. E7 induced anchorage-independent growth in SOCS1-deficient fibroblasts, but not in wild-type cells. These data suggested that SOCS1 plays an important role in regulating the levels of E7 protein and their transforming potential, and could be a new therapeutic tool for HPV-mediated tumors.
Kamio
Masaki
M
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Yoshida
Takafumi
T
Ogata
Hisanobu
H
Douchi
Tsutomu
T
Nagata
Yukihiro
Y
Inoue
Makoto
M
Hasegawa
Mamoru
M
Yonemitsu
Yoshikazu
Y
Yoshimura
Akihiko
A
D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D017931:DNA Primers; D021901:DNA, Intergenic / Q000235:genetics; D005260:Female; D005822:Genetic Vectors; D006367:HeLa Cells / Q000637:transplantation; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009097:Multienzyme Complexes / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D046988:Proteasome Endopeptidase Complex; D015183:Restriction Mapping; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014183:Transplantation, Heterologous; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology* / Q000821:virology
D017931:DNA Primers; D021901:DNA, Intergenic; D009097:Multienzyme Complexes; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein; C059731:oncogene protein E7, Human papillomavirus type 16; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex