RelA-Induced Interferon Response Negatively Regulates Proliferation.
Both oncogenic and tumor-suppressor activities are attributed to the Nuclear Factor kappa B (NF-kB) pathway. Moreover, NF-kB may positively or negatively regulate proliferation. The molecular determinants of these opposing roles of NF-kB are unclear. Using primary human mammary epithelial cells (HME...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0140243&type=printable |
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| author | Bose S Kochupurakkal Zhigang C Wang Tony Hua Aedin C Culhane Scott J Rodig Koraljka Rajkovic-Molek Jean-Bernard Lazaro Andrea L Richardson Debajit K Biswas J Dirk Iglehart |
| author_facet | Bose S Kochupurakkal Zhigang C Wang Tony Hua Aedin C Culhane Scott J Rodig Koraljka Rajkovic-Molek Jean-Bernard Lazaro Andrea L Richardson Debajit K Biswas J Dirk Iglehart |
| author_sort | Bose S Kochupurakkal |
| collection | DOAJ |
| description | Both oncogenic and tumor-suppressor activities are attributed to the Nuclear Factor kappa B (NF-kB) pathway. Moreover, NF-kB may positively or negatively regulate proliferation. The molecular determinants of these opposing roles of NF-kB are unclear. Using primary human mammary epithelial cells (HMEC) as a model, we show that increased RelA levels and consequent increase in basal transcriptional activity of RelA induces IRF1, a target gene. Induced IRF1 upregulates STAT1 and IRF7, and in consort, these factors induce the expression of interferon response genes. Activation of the interferon pathway down-regulates CDK4 and up-regulates p27 resulting in Rb hypo-phosphorylation and cell cycle arrest. Stimulation of HMEC with IFN-γ elicits similar phenotypic and molecular changes suggesting that basal activity of RelA and IFN-γ converge on IRF1 to regulate proliferation. The anti-proliferative RelA-IRF1-CDK4 signaling axis is retained in ER+/HER2- breast tumors analyzed by The Cancer Genome Atlas (TCGA). Using immuno-histochemical analysis of breast tumors, we confirm the negative correlation between RelA levels and proliferation rate in ER+/HER2- breast tumors. These findings attribute an anti-proliferative tumor-suppressor role to basal RelA activity. Inactivation of Rb, down-regulation of RelA or IRF1, or upregulation of CDK4 or IRF2 rescues the RelA-IRF1-CDK4 induced proliferation arrest in HMEC and are points of disruption in aggressive tumors. Activity of the RelA-IRF1-CDK4 axis may explain favorable response to CDK4/6 inhibition observed in patients with ER+ Rb competent tumors. |
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| format | Article |
| id | doaj.art-e2c8ac55fb3a48a5adfcf77cafd2d682 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2025-03-14T15:35:13Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj.art-e2c8ac55fb3a48a5adfcf77cafd2d6822025-02-25T05:33:47ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-011010e014024310.1371/journal.pone.0140243RelA-Induced Interferon Response Negatively Regulates Proliferation.Bose S KochupurakkalZhigang C WangTony HuaAedin C CulhaneScott J RodigKoraljka Rajkovic-MolekJean-Bernard LazaroAndrea L RichardsonDebajit K BiswasJ Dirk IglehartBoth oncogenic and tumor-suppressor activities are attributed to the Nuclear Factor kappa B (NF-kB) pathway. Moreover, NF-kB may positively or negatively regulate proliferation. The molecular determinants of these opposing roles of NF-kB are unclear. Using primary human mammary epithelial cells (HMEC) as a model, we show that increased RelA levels and consequent increase in basal transcriptional activity of RelA induces IRF1, a target gene. Induced IRF1 upregulates STAT1 and IRF7, and in consort, these factors induce the expression of interferon response genes. Activation of the interferon pathway down-regulates CDK4 and up-regulates p27 resulting in Rb hypo-phosphorylation and cell cycle arrest. Stimulation of HMEC with IFN-γ elicits similar phenotypic and molecular changes suggesting that basal activity of RelA and IFN-γ converge on IRF1 to regulate proliferation. The anti-proliferative RelA-IRF1-CDK4 signaling axis is retained in ER+/HER2- breast tumors analyzed by The Cancer Genome Atlas (TCGA). Using immuno-histochemical analysis of breast tumors, we confirm the negative correlation between RelA levels and proliferation rate in ER+/HER2- breast tumors. These findings attribute an anti-proliferative tumor-suppressor role to basal RelA activity. Inactivation of Rb, down-regulation of RelA or IRF1, or upregulation of CDK4 or IRF2 rescues the RelA-IRF1-CDK4 induced proliferation arrest in HMEC and are points of disruption in aggressive tumors. Activity of the RelA-IRF1-CDK4 axis may explain favorable response to CDK4/6 inhibition observed in patients with ER+ Rb competent tumors.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0140243&type=printable |
| spellingShingle | Bose S Kochupurakkal Zhigang C Wang Tony Hua Aedin C Culhane Scott J Rodig Koraljka Rajkovic-Molek Jean-Bernard Lazaro Andrea L Richardson Debajit K Biswas J Dirk Iglehart RelA-Induced Interferon Response Negatively Regulates Proliferation. PLoS ONE |
| title | RelA-Induced Interferon Response Negatively Regulates Proliferation. |
| title_full | RelA-Induced Interferon Response Negatively Regulates Proliferation. |
| title_fullStr | RelA-Induced Interferon Response Negatively Regulates Proliferation. |
| title_full_unstemmed | RelA-Induced Interferon Response Negatively Regulates Proliferation. |
| title_short | RelA-Induced Interferon Response Negatively Regulates Proliferation. |
| title_sort | rela induced interferon response negatively regulates proliferation |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0140243&type=printable |
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