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

• Published in: Leukemia Vol. 31; no. 10; pp. 2235 - 2243
• Main Authors: Terol, M, Gazon, H, Lemasson, I, Duc-Dodon, M, Barbeau, B, Césaire, R, Mesnard, J-M, Péloponèse Jr, J-M
• Format: Journal Article Web Resource
• Language: English
• Published: London Nature Publishing Group UK 01-10-2017; Nature Publishing Group; Springer Nature
• Subjects: 13/109; 13/89; 38/90; 631/67/1858; 631/67/395; 82/29; 82/80; Activator protein 1; Basic-Leucine Zipper Transcription Factors; Basic-Leucine Zipper Transcription Factors - physiology; Biological Transport; Bypasses; Cancer Research; Care and treatment; Cell Line; Cell Nucleus; Cell Nucleus - metabolism; Cell proliferation; Cell Transformation, Viral; Cell Transformation, Viral - genetics; Critical Care Medicine; Culture Media, Serum-Free; Deprivation; Deregulation; Development and progression; Gene expression; Gene Expression Regulation, Leukemic; Gene Expression Regulation, Leukemic - genetics; Gene Expression Regulation, Viral; Gene Expression Regulation, Viral - genetics; Genetic aspects; Genetic transformation; HBZ gene; HBZ protein, human T-cell leukemia virus type I; Health aspects; HEK293 cell line; HEK293 Cells; Hematology; HTLV-1 infection; HTLV-I Infections; HTLV-I Infections - blood; Human health sciences; Humans; Intensive; Internal Medicine; Isoforms; JunD gene; JunD protein, human; Leucine; Leucine zipper proteins; Leukemia; Life Sciences; Lymphocytes; Lymphocytes T; Machinery and equipment; Medicine; Medicine & Public Health; MEN1 protein, human; Microbiology and Parasitology; Oncologie; Oncology; original-article; Protein Biosynthesis; Protein Biosynthesis - genetics; Protein Isoforms; Protein Isoforms - genetics; Protein Isoforms - physiology; Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-jun; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - physiology; Retroviridae Proteins; Retroviridae Proteins - physiology; Ribosomal Proteins; Ribosomal Proteins - antagonists & inhibitors; Ribosomal Proteins - genetics; Ribosomes; Ribosomes - metabolism; RNA, Messenger; RNA, Messenger - metabolism; RPS25 gene; RPS25 protein, human; Sciences de la santé humaine; T lymphocyte; T-Lymphocytes; T-Lymphocytes - pathology; T-Lymphocytes - virology; Transcription factors; Transfection; Translation; Translation initiation; Tumor suppressor genes; Tumors; Virology; Viruses
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/leu.2017.74

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 and activate 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 Δ 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 Δ JunD isoform. We demonstrate that, unlike JunD, Δ JunD induces proliferation and transformation of cells. To decipher the mechanisms for Δ 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 the small ribosomal subunit. Therefore, HBZ bypasses translational control of JunD uORF and favors the expression of Δ JunD. In conclusion, we provide strong evidences that HBZ induces Δ JunD expression through alteration of the cellular translational machinery and that the truncated isoform Δ JunD has a central role in the oncogenic process leading to ATL.