TY - JOUR
T1 - A fail-safe system to prevent oncogenesis by senescence is targeted by SV40 small T antigen
AU - Oshikawa, Kiyotaka
AU - Matsumoto, Masaki
AU - Kodama, Manabu
AU - Shimizu, Hideyuki
AU - Nakayama, Keiichi I.
N1 - Funding Information:
Acknowledgements We thank T. Akagi for the pCX4 system as well as hTERT, SV40 ER, and H-RasG12V expression vectors; A. Sakiyama and K. Tsunematsu for technical assistance; members of our laboratories for comments on the manuscript; and A. Ohta for help in preparation of the manuscript. This work was supported in part by KAKENHI grants from Japan Society for the Promotion of Science (JSPS) and the Ministry of Education, Culture, Sports, Science, and Technology of Japan to KIN (18H05215, 17H06301, and 25221303) and to MM (17K19606, 17H05534, and 17H06011) as well as by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) of the Japan Agency for Medical Research and Development (AMED). MM is also supported by Core Research for Evolutionary Science and Technology (CREST, JPMJCR15G4) of the Japan Science and Technology Agency (JST).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/3/5
Y1 - 2020/3/5
N2 - Whereas large T antigen (LT) of simian virus 40 (SV40) promotes oncogenesis by inactivating the tumor suppressor proteins p53 and pRb, SV40 small T antigen (ST) has been thought to be dispensable for this process. However, here we show that LT promotes both oncogenic growth and senescence in human cells expressing oncogenic Ras and that this latter effect is antagonized by ST. Inactivation of p53 by LT alone promoted the senescence-associated secretory phenotype (SASP), whereas the additional expression of ST attenuated this phenotype, allowing cells to avoid oncogene-induced senescence (OIS) and thereby promoting efficient oncogenesis. ST interacts with and inhibits the function of heterochromatin protein 1–binding protein 3 (HP1BP3), a positive regulator of global microRNA biogenesis, and it thereby triggers aberrant upregulation of B-cell translocation gene 2 (BTG2), which is essential for prevention of SASP and OIS by ST. Collectively, our results indicate that the HP1BP3-BTG2 axis constitutes a fail-safe system to prevent oncogenesis by means of OIS induction, and that this system is hijacked by ST.
AB - Whereas large T antigen (LT) of simian virus 40 (SV40) promotes oncogenesis by inactivating the tumor suppressor proteins p53 and pRb, SV40 small T antigen (ST) has been thought to be dispensable for this process. However, here we show that LT promotes both oncogenic growth and senescence in human cells expressing oncogenic Ras and that this latter effect is antagonized by ST. Inactivation of p53 by LT alone promoted the senescence-associated secretory phenotype (SASP), whereas the additional expression of ST attenuated this phenotype, allowing cells to avoid oncogene-induced senescence (OIS) and thereby promoting efficient oncogenesis. ST interacts with and inhibits the function of heterochromatin protein 1–binding protein 3 (HP1BP3), a positive regulator of global microRNA biogenesis, and it thereby triggers aberrant upregulation of B-cell translocation gene 2 (BTG2), which is essential for prevention of SASP and OIS by ST. Collectively, our results indicate that the HP1BP3-BTG2 axis constitutes a fail-safe system to prevent oncogenesis by means of OIS induction, and that this system is hijacked by ST.
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U2 - 10.1038/s41388-019-1139-1
DO - 10.1038/s41388-019-1139-1
M3 - Article
C2 - 31819167
AN - SCOPUS:85076351825
SN - 0950-9232
VL - 39
SP - 2170
EP - 2186
JO - Oncogene
JF - Oncogene
IS - 10
ER -
