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Identification of E2F1 as an important transcription factor for the regulation of tapasin expression.

ABSTRACT: HER-2/neu overexpression in tumor cells caused abnormalities of MHC class I surface expression due to impaired expression of components of the antigen-processing machinery (APM) including the low molecular weight proteins, the transporter associated with antigen processing (TAP), and the chaperone tapasin, whereas the expression of MHC class I heavy chain as well as ?(2)-microglobulin was only marginally affected. This oncogene-mediated deficient APM component expression could be reverted by interferon-? treatment, suggesting a deregulation rather than structural alterations as underlying molecular mechanisms. To determine the level of regulation, the transcriptional activity of APM components was analyzed in HER-2/neu(-) and HER-2/neu(+) cells. All major APM components were transcriptionally down-regulated in HER-2/neu(+) when compared with HER-2/neu(-) cells, which was accompanied by a reduced binding of RNA polymerase II to the APM promoters. Site-directed mutagenesis of the p300- and E2F-binding sites in the APM promoters did not reconstitute the oncogene-mediated decreased transcription rate with the exception of tapasin, which was restored in HER-2/neu(+) cells to levels of wild type tapasin promoter activity in HER-2/neu(-) fibroblasts. The E2F-directed control of tapasin expression was further confirmed by chromatin immunoprecipitation analyses showing that E2F1 and p300 bind to the tapasin and APM promoters in both cell lines. Moreover, siRNA-mediated silencing of E2F1 was associated with an increased tapasin expression, whereas transient overexpression of E2F1 launch a reduced tapasin transcription, suggesting that E2F1 is an essential transcription factor for tapasin.

SUBMITTER: Bukur J

PROVIDER: S-EPMC2945534 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Identification of E2F1 as an important transcription factor for the regulation of tapasin expression.

Bukur Juergen J Herrmann Felix F Handke Diana D Recktenwald Christian C Seliger Barbara B

The Journal of biological chemistry 20100727 40

HER-2/neu overexpression in tumor cells caused abnormalities of MHC class I surface expression due to impaired expression of components of the antigen-processing machinery (APM) including the low molecular weight proteins, the transporter associated with antigen processing (TAP), and the chaperone tapasin, whereas the expression of MHC class I heavy chain as well as β(2)-microglobulin was only marginally affected. This oncogene-mediated deficient APM component expression could be reverted by int ...[more]

PMID: 20663889

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Project description:The E2F family of transcription factors plays an important role in the control of the cell cycle, cell proliferation, and differentiation, and their role in ovarian function is just emerging. Although some evidence suggests a possible role of E2F1 in ovarian follicular development, what regulates its production in ovarian cells is unknown. Objectives of this study were to determine whether: (i) E2F1 gene expression in granulosa cells (GCs) and theca cells (TCs) change with follicular development and (ii) E2F1 mRNA abundance in TC and GC is hormonally regulated. Using real-time PCR, E2F1 mRNA abundance in GC was 5.5-fold greater (P?<?0.05) in small (SM; 1 to 5 mm) than large (LG; >8 mm) follicles, but in TC, E2F1 expression did not differ among follicle sizes. SM-follicle GC had 2.1-fold greater (P?<?0.05) E2F1 mRNA than TC. In SM-follicle GC, FGF9 induced a 7.6-fold increase in E2F1 mRNA abundance; however, FGF9 did not affect (P?>?0.10) abundance of E2F1 mRNA in LG-follicle TC or GC. Follicle-stimulating hormone (FSH) had no effect (P?>?0.10) on E2F1 gene expression in SM- or LG-follicle GC. SM-follicle GC were concomitantly treated with insulin-like growth factor 1 (30 ng/mL), FSH (30 ng/mL), and either 0 or 30 ng/mL of FGF9 with or without 50 µM of an E2F inhibitor (E2Fi; HLM0064741); FGF9 alone increased (P?<?0.05) GC numbers, whereas E2Fi alone decreased (P?<?0.05) GC numbers, and concomitant treatment of E2Fi with FGF9 blocked (P?<?0.05) this stimulatory effect of FGF9. Estradiol production was inhibited (P?<?0.05) by FGF9 alone and concomitant treatment of E2Fi with FGF9 attenuated (P?<?0.05) this inhibitory effect of FGF9. SM-follicle GC treated with E2Fi decreased (P?<?0.05) E2F1 mRNA abundance by 70%. Collectively, our studies show that GC E2F1 mRNA is developmentally and hormonally regulated in cattle. Inhibition of E2F1 reduced FGF9-induced GC proliferation and attenuated FGF9-inhibited estradiol production, indicating that E2F1 may be involved in follicular development in cattle.

Dataset Information

Identification of E2F1 as an important transcription factor for the regulation of tapasin expression.

Publications

Identification of E2F1 as an important transcription factor for the regulation of tapasin expression.

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