Abstract
Telomerase activity in cancer cells is dependent on the transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene, encoding the catalytic subunit of human telomerase. We have shown previously that HTLV-1 basic leucine zipper (HBZ), a viral regulatory protein encoded by the human retrovirus, human T-cell leukemia virus, type 1 (HTLV-1) cooperates with JunD to enhance hTERT transcription in adult T-cell leukemia (ATL) cells. Menin, the product of the tumor-suppressor MEN-1 gene, also interacts with JunD, represses its transcriptional activity and downregulates telomerase expression. The main objective of this study was to examine how menin and HBZ get involved in the regulation of hTERT transcription. In this study, we report that JunD and menin form a repressor complex of hTERT transcription in HBZ-negative cells. Conversely, in HBZ-positive cells, the formation of a JunD/HBZ/menin ternary complex and the recruitment of p300 histone acetyl transferase activity by HBZ lead to a decreased activity of the JunD-menin suppressor unit that correlates with the activation of hTERT transcription. Silencing HBZ or menin expression in ATL cells confirms that these proteins are differentially involved in telomerase regulation. These results propose that HBZ, by impeding the tumor-suppressor activity of menin, functions as a leukemogenic cofactor to upregulate gene transcription and promote JunD-mediated leukemogenesis.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Basic-Leucine Zipper Transcription Factors / antagonists & inhibitors
-
Basic-Leucine Zipper Transcription Factors / genetics
-
Basic-Leucine Zipper Transcription Factors / metabolism*
-
Blotting, Western
-
Cell Proliferation
-
Chromatin Immunoprecipitation
-
E1A-Associated p300 Protein / genetics
-
E1A-Associated p300 Protein / metabolism*
-
Gene Expression Regulation, Neoplastic*
-
HeLa Cells
-
Humans
-
Immunoprecipitation
-
Leukemia, T-Cell / genetics
-
Leukemia, T-Cell / metabolism
-
Leukemia, T-Cell / pathology*
-
Promoter Regions, Genetic / genetics
-
Proto-Oncogene Proteins / antagonists & inhibitors
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism*
-
Proto-Oncogene Proteins c-jun / genetics
-
Proto-Oncogene Proteins c-jun / metabolism*
-
RNA, Messenger / genetics
-
RNA, Small Interfering / genetics
-
Real-Time Polymerase Chain Reaction
-
Retroviridae Proteins
-
Reverse Transcriptase Polymerase Chain Reaction
-
Telomerase / genetics*
-
Telomerase / metabolism
-
Transcription, Genetic
-
Tumor Cells, Cultured
-
Viral Proteins / antagonists & inhibitors
-
Viral Proteins / genetics
-
Viral Proteins / metabolism*
Substances
-
Basic-Leucine Zipper Transcription Factors
-
HBZ protein, human T-cell leukemia virus type I
-
JunD protein, human
-
MEN1 protein, human
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-jun
-
RNA, Messenger
-
RNA, Small Interfering
-
Retroviridae Proteins
-
Viral Proteins
-
E1A-Associated p300 Protein
-
EP300 protein, human
-
TERT protein, human
-
Telomerase