title: Activation of the long terminal repeat of human endogenous retrovirus K by melanoma-specific transcription factor MITF-M.
abstract: The human and Old World primate genomes possess conserved endogenous retrovirus sequences that have been implicated in evolution, reproduction, and carcinogenesis. Human endogenous retrovirus (HERV)-K with 5'LTR-gag-pro-pol-env-rec/np9-3'LTR sequences represents the newest retrovirus family that integrated into the human genome 1 to 5 million years ago. Although a high-level expression of HERV-K in melanomas, breast cancers, and teratocarcinomas has been demonstrated, the mechanism of the lineage-specific activation of the long terminal repeat (LTR) remains obscure. We studied chromosomal HERV-K expression in MeWo melanoma cells in comparison with the basal expression in human embryonic kidney 293 (HEK293) cells. Cloned LTR of HERV-K (HML-2.HOM) was also characterized by mutation and transactivation experiments. We detected multiple transcriptional initiator (Inr) sites in the LTR by rapid amplification of complementary DNA ends (5' RACE). HEK293 and MeWo showed different Inr usage. The most potent Inr was associated with a TATA box and three binding motifs of microphthalmia-associated transcription factor (MITF). Both chromosomal HERV-K expression and the cloned LTR function were strongly activated in HEK293 by transfection with MITF-M, a melanocyte/melanoma-specific isoform of MITF. Coexpression of MITF and the HERV-K core antigen was detected in retinal pigmented epithelium by an immunofluorescence analysis. Although malignant melanoma lines MeWo, G361, and SK-MEL-28 showed enhanced HERV-K transcription compared with normal melanocytes, the level of MITF-M messenger RNA persisted from normal to transformed melanocytes. Thus, MITF-M may be a prerequisite for the pigmented cell lineage-specific function of HERV-K LTR, leading to the high-level expression in malignant melanomas.
authors: Department of Microbiology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan. iyoko@yamanashi.ac.jp
authors: Iyoko
authors: I
authors: Katoh
authors: Anna
authors: A
authors: Mírová
authors: Shun-ichi
authors: S
authors: Kurata
authors: Yasushi
authors: Y
authors: Murakami
authors: Kenji
authors: K
authors: Horikawa
authors: Natsuko
authors: N
authors: Nakakuki
authors: Takunobu
authors: T
authors: Sakai
authors: Kunihiko
authors: K
authors: Hashimoto
authors: Ayako
authors: A
authors: Maruyama
authors: Takaaki
authors: T
authors: Yonaga
authors: Nahoko
authors: N
authors: Fukunishi
authors: Kohji
authors: K
authors: Moriishi
authors: Hirohisa
authors: H
authors: Hirai
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D020077:Endogenous Retroviruses / Q000235:genetics*; D005260:Female; D005333:Fetus / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D052138:Genes, Neoplasm / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008545:Melanoma / Q000235:genetics; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D012878:Skin Neoplasms / Q000235:genetics; D020079:Terminal Repeat Sequences / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D051739:Microphthalmia-Associated Transcription Factor