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Molecular dissection on inhibition of Ras-induced cellular senescence by small t antigen of SV40

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Abstract

Simian virus 40 (SV40) is a potentially oncogenic virus of monkey origin. Transmission, prevalence, and pathogenicity rates of SV40 are unclear, but infection can occur in humans, for example individuals with high contact with rhesus macaques and individuals that received contaminated early batches of polio vaccines in 1950–1963. In addition, several human polyomaviruses, proven carcinogenic, are also highly common in global populations. Cellular senescence is a major mechanism of cancer prevention in vivo. Hyperactivation of Ras usually induces cellular senescence rather than cell transformation. Previous studies suggest small t antigen (ST) of SV40 may interfere with cellular senescence induced by Ras. In the current study, ST was demonstrated to inhibit Ras-induced cellular senescence (RIS) and accumulation of DNA damage in Ras-activated cells. In addition, ST suppressed the signal transmission from BRaf to MEK and thus blocked the downstream transmission of the activated Ras signal. B56γ knockdown mimicked the inhibitory effects of ST overexpression on RIS. Furthermore, KSR1 knockdown inhibited Ras activation and the subsequent cellular senescence. Further mechanism studies indicated that the phosphorylation level of KSR1 rather than the levels of the total protein regulates the activation of Ras signaling pathway. In sum, ST inhibits the continuous hyperactivation of Ras signals by interfering with the normal functions of PP2A-B56γ of dephosphorylating KSR1, thus inhibiting the occurrence of cellular senescence. Although the roles of SV40 in human carcinogenesis are controversial so far, our study has shown that ST of polyomaviruses has tumorigenic potential by inhibiting oncogene-induced senescence (OIS) as a proof of concept.

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Acknowledgements

We would like to thank Prof. Rugang Zhang at the Wistar Institute for his great help and suggestions.

Funding

This work was supported by the National Natural Science Foundation 31771521 (to Z. Tu) and 81672582 (to H. Liu); Top Talent of Innovative Research Team of Jiangsu Province (to H. Liu and Z. Tu); Senior Talent Start-up Funds of Jiangsu University 14JDG050 (to H. Liu) and 14JDG011 (to Z. Tu).

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Authors and Affiliations

  1. School of Life Sciences, Jiangsu University, Zhenjiang, 212013, Jiangsu, China

    Dongsheng Shang, Tianchu Zhou, Yanfang Wu & Zhigang Tu

  2. School of Chinese Material Medica, Yunnan University of Chinese Medicine, Kunming, 650500, Yunnan, China

    Xinying Zhuang

  3. School of Pharmacy, Jiangsu University, Zhenjiang, 212013, Jiangsu, China

    Hanqing Liu

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  1. Dongsheng Shang
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  2. Tianchu Zhou
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  3. Xinying Zhuang
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  4. Yanfang Wu
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Contributions

Project administration, supervision, funding acquisition and provision, and writing the original draft were accomplished by ZT and HL. Conceptualization and methodology were accomplished by ZT, HL, and XZ. DS, TZ, and YW were responsible for investigation, data curation, and analysis.

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Correspondence to Hanqing Liu or Zhigang Tu.

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Shang, D., Zhou, T., Zhuang, X. et al. Molecular dissection on inhibition of Ras-induced cellular senescence by small t antigen of SV40. Cell. Mol. Life Sci. 79, 242 (2022). https://doi.org/10.1007/s00018-022-04275-5

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