PMID:21300782

Citation	Qi, DL, Ohhira, T, Fujisaki, C, Inoue, T, Ohta, T, Osaki, M, Ohshiro, E, Seko, T, Aoki, S, Oshimura, M and Kugoh, H (2011) Identification of PITX1 as a TERT suppressor gene located on human chromosome 5. Mol. Cell. Biol. 31:1624-36
Abstract	Telomerase, a ribonucleoprotein enzyme that maintains telomere length, is crucial for cellular immortalization and cancer progression. Telomerase activity is attributed primarily to the expression of telomerase reverse transcriptase (TERT). Using microcell-mediated chromosome transfer (MMCT) into the mouse melanoma cell line B16F10, we previously found that human chromosome 5 carries a gene, or genes, that can negatively regulate TERT expression (H. Kugoh, K. Shigenami, K. Funaki, J. Barrett, and M. Oshimura, Genes Chromosome Cancer 36:37-47, 2003). To identify the gene responsible for the regulation of TERT transcription, we performed cDNA microarray analysis using parental B16F10 cells, telomerase-negative B16F10 microcell hybrids with a human chromosome 5 (B16F10MH5), and its revertant clones (MH5R) with reactivated telomerase. Here, we report the identification of PITX1, whose expression leads to the downregulation of mouse tert (mtert) transcription, as a TERT suppressor gene. Additionally, both human TERT (hTERT) and mouse TERT (mtert) promoter activity can be suppressed by PITX1. We show that three and one binding site within the hTERT and mtert promoters, respectively, that express a unique conserved region are responsible for the transcriptional activation of TERT. Furthermore, we showed that PITX1 binds to the TERT promoter both in vitro and in vivo. Thus, PITX1 suppresses TERT transcription through direct binding to the TERT promoter, which ultimately regulates telomerase activity.
Links	PubMed PMC3126332 Online version:10.1128/MCB.00470-10
Keywords	Animals; Cell Line, Tumor; Chromosomes, Human, Pair 5; Humans; Mice; Molecular Sequence Data; Paired Box Transcription Factors/genetics; Paired Box Transcription Factors/metabolism; Promoter Regions, Genetic; Protein Binding; RNA, Messenger/genetics; Sequence Alignment; Sequence Homology, Nucleic Acid; Telomerase/genetics; Telomerase/metabolism; Transcription, Genetic
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:PITX1		GO:0045892: negative regulation of transcription, DNA-dependent	ECO:0000315:		P		Figure 3 shows that TERT expression levels are decreased when PITX1 expression is high. Figure 4 further details that TERT expression is controlled through PITX1 binding to the promoter region of TERT.	complete CACAO 7263
MOUSE:PITX1	involved_in	GO:0045892: negative regulation of transcription, DNA-templated	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

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