Biffi Renato, Benoit Stefanie W, Sariyer Ilker K, Safak Mahmut
Eurofins Biolabs S.R.L, Via Brubno Buozzi 2, Vimodrone, MI, 20055, Italy.
University of Cincinnati, Cincinnati Children's Hospital Medical Center, Burnet Campus, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
Tumour Virus Res. 2024 Dec;18:200298. doi: 10.1016/j.tvr.2024.200298. Epub 2024 Nov 23.
The early coding region of JC virus (JCV) encodes several regulatory proteins including large T antigen (LT-Ag), small t antigen (Sm t-Ag) and T' proteins because of the alternative splicing of the pre-mRNA. LT-Ag plays a critical role in cell transformation by targeting the key cell cycle regulatory proteins including p53 and pRb, however, the role of Sm t-Ag in this process remains elusive. Here, we investigated the effect of Sm t-Ag on the cell cycle progression and demonstrated that it facilitates S phase entry and exit when cells are released from G0/G1 growth arrest. Examination of the cell cycle stage specific expression profiles of the selected cyclins and cyclin-dependent kinases, including those active at the G1/S and G2/M transition state, demonstrated a higher level of early expression of these regulators such as cyclin B, cycling E, and Cdk2. In addition, analysis of the effect of Sm t-Ag on the growth promoting pathways including those active in the PI3K/Akt/mTOR axis showed substantially higher levels of the phosphorylated-Akt, -Gsk3-β and -S6K1 in Sm t-Ag-positive cells. Collectively, our results demonstrate that Sm t-Ag promotes cell cycle progression by activating the growth promoting pathways through which it may contribute to LT-Ag-mediated cell transformation.
由于前体mRNA的可变剪接，JC病毒（JCV）的早期编码区编码几种调节蛋白，包括大T抗原（LT-Ag）、小t抗原（Sm t-Ag）和T'蛋白。LT-Ag通过靶向包括p53和pRb在内的关键细胞周期调节蛋白在细胞转化中起关键作用，然而，Sm t-Ag在此过程中的作用仍不清楚。在此，我们研究了Sm t-Ag对细胞周期进程的影响，并证明当细胞从G0/G1生长停滞中释放时，它促进S期的进入和退出。对选定的细胞周期蛋白和细胞周期蛋白依赖性激酶的细胞周期阶段特异性表达谱进行检测，包括那些在G1/S和G2/M转变状态下活跃的蛋白，结果显示这些调节因子如细胞周期蛋白B、细胞周期蛋白E和细胞周期蛋白依赖性激酶2（Cdk2）的早期表达水平更高。此外，对Sm t-Ag对包括那些在PI3K/Akt/mTOR轴中活跃的生长促进途径的影响进行分析，结果显示Sm t-Ag阳性细胞中磷酸化的Akt、糖原合成酶激酶3-β（Gsk3-β）和核糖体蛋白S6激酶1（S6K）的水平显著更高。总的来说，我们的结果表明，Sm t-Ag通过激活生长促进途径促进细胞周期进程，它可能通过这些途径促进LT-Ag介导的细胞转化。
