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HBZ-mediated shift of JunD from growth suppressor to tumor promoter in leukemic cells by inhibition of ribosomal protein S25 expression.

M Terol, H Gazon, I Lemasson, M Duc-Dodon, B Barbeau, R Cesaire, J-M Mesnard, and J-M J Peloponese (2017)

Leukemia.

Human T-cell leukemia virus type 1 (HTLV-1) basic-leucine zipper (bZIP) factor (HBZ) is a key player in proliferation and transformation of HTLV-1-infected cells, thus contributing to adult T-cell leukemia (ATL) development. HBZ deregulates gene expression within the host cell by interacting with several cellular partners. Through its C-terminal ZIP domain, HBZ is able to contact andactivate JunD, a transcription factor of the AP-1 family. JunD mRNA is intronless but can generate two protein isoforms by alternative translation initiation: JunD full-length and Delta JunD, an N-terminal truncated form unresponsive to the tumor suppressor menin. Using various cell lines and primary T-lymphocytes, we show that after serum deprivation HBZ induces the expression of Delta JunD isoform. We demonstrate that, unlike JunD, Delta JunD induces proliferation and transformation of cells. To decipher the mechanisms for Delta JunD production, we looked into the translational machinery and observed that HBZ induces nuclear retention of RPS25 mRNA and loss of RPS25 protein expression, a component of thesmall ribosomal subunit. Therefore, HBZ bypasses translational control of JunD uORF and favors the expression of Delta JunD. In conclusion, we provide strong evidences that HBZ induces Delta JunD expression through alteration of the cellular translational machinery and that the truncated isoform Delta JunD has acentral role in the oncogenic process leading to ATL.Leukemia advance online publication, 24 March 2017; doi:10.1038/leu.2017.74.

 
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