TCEAL7, a putative tumor suppressor gene, negatively regulates NF-B pathway

R. Rattan, K. Narita, J. Chien, J. L. Maguire, R. Shridhar, S. Giri, V. Shridhar

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

We have previously shown that a frequently downregulated gene, transcription elongation factor A-like 7 (TCEAL7), promoted anchorage- independent growth and modulated Myc activity in ovarian surface epithelial cells immortalized with temperature-sensitive large T antigen and human telomerase reverse transcriptase (OSEtsT/hTERT). Analysis of protein/DNA array showed that TCEAL7 downregulation resulted in an approximately twofold increase in nuclear factor (NF)-B binding to its target DNA sequence. In this study we showed that short hairpin RNA (shRNA)-mediated downregulation of TCEAL7 in two different immortalized OSE cells showed higher NF-B activity, as determined using reporter and gel-shift assays. Transient transfection of TCEAL7 inhibited the activation of NF-B in TCEAL7-downregulated clones, IOSE-523 and in other ovarian cancer cell lines (OVCAR8, SKOV3ip and DOV13), suggesting that TCEAL7 negatively regulates NF-B pathway. Consistent with this observation, TCEAL7-downregulated clones showed higher levels of NF-B targets, such as pro-proliferative (cyclin-D1 and cMyc), pro-angiogenic (interleukin (IL)-6, IL-8 and vascular endothelial growth factor (VEGF)), inflammatory (intercellular adhesion molecule 1 (ICAM-1) and cyclooxygenase-2 (Cox-2)) and anti-apoptotic (B-cell lymphoma-extra large (Bcl-xl)) genes when compared with vector controls. Inhibition of NF-B by IB kinase (IKK) inhibitor (BMS 345541) attenuated cell survival and proliferation of TCEAL-knockdown clones. Although TCEAL7 inhibited p65 transcriptional activity, it did not modulate the cytoplasmic signaling of the NF-B pathway, by itself or by tumor necrosis factor-α (TNF-α). Chromatin immunoprecipitation (ChIP) assays revealed increased recruitment of p65 and p300 to the promoters of IL-8 and IL-6 in TCEAL7-downregulated clones. Collectively, these results indicate a novel role for TCEAL7 in the negative regulation of NF-B signaling at the basal level by modulating transcriptional activity of NF-B on its target gene promoters, potentially providing a novel mechanism by which NF-B activity may be deregulated in ovarian cancer cells.

Original languageEnglish (US)
Pages (from-to)1362-1373
Number of pages12
JournalOncogene
Volume29
Issue number9
DOIs
StatePublished - Mar 1 2010
Externally publishedYes

Keywords

  • NF-kB
  • Ovarian cancer
  • TCEAL7
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Rattan, R., Narita, K., Chien, J., Maguire, J. L., Shridhar, R., Giri, S., & Shridhar, V. (2010). TCEAL7, a putative tumor suppressor gene, negatively regulates NF-B pathway. Oncogene, 29(9), 1362-1373. https://doi.org/10.1038/onc.2009.431