Journal
JOURNAL OF CELL SCIENCE
Volume 131, Issue 10, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.210906
Keywords
BAMBI; Polarity; Hypoxia; TGF beta pathway; HIF1
Categories
Funding
- Academy of Finland Research Council for Health [114344, 296498, 135560, 263770]
- Academy of Finland Center of Excellence [251314]
- Sigrid Juseliuksen Saatio
- Jane ja Aatos Erkon Saatio
- FibroGen Inc.
- Academy of Finland (AKA) [263770, 114344, 263770, 114344] Funding Source: Academy of Finland (AKA)
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Hypoxia and loss of cell polarity are common features of malignant carcinomas. Hypoxia-inducible factor 1 (HIF1) is the major regulator of cellular hypoxia response and mediates the activation of similar to 300 genes. Increased HIF1 signaling is known to be associated with epithelial-mesenchymal transformation. Here, we report that hypoxia disrupts polarized epithelial morphogenesis of MDCK cells in a HIF1 alpha-dependent manner by modulating the transforming growth factor-beta (TGF beta) signaling pathway. Analysis of potential HIF1 targets in the TGF beta pathway identified the bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), a transmembrane glycoprotein related to the type I receptors of the TGF beta family, whose expression was essentially lost in HIF1-depleted cells. Similar to what was observed in HIF1-deficient cells, BAMBI-depleted cells failed to efficiently activate TGF beta signaling and retained epithelial polarity during hypoxia. Taken together, we show that hypoxic conditions promote TGF beta signaling in a HIF1-dependent manner and BAMBI is identified in this pathway as a novel HIF1-regulated gene that contributes to hypoxia-induced loss of epithelial polarity.
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