BAMBI is a novel HIF1-dependent modulator of TGFβ-mediated disruption of cell polarity during hypoxia

Abstract

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 ∼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 HIF1α-dependent manner by modulating the transforming growth factor-β (TGFβ) signaling pathway. Analysis of potential HIF1 targets in the TGFβ pathway identified the bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), a transmembrane glycoprotein related to the type I receptors of the TGFβ 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 TGFβ signaling and retained epithelial polarity during hypoxia. Taken together, we show that hypoxic conditions promote TGFβ 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.

Verteporfin treatment controls morphology, phenotype, and global gene expression for cells of the human nucleus pulposus

“…Examining the expression of genes within the ontology term Regulation of Cell Shape (GO: 0008360) provides insight into the mechanisms by which cell shape may be driving NP phenotype. While the expression profiles of the genes GNA13, BAMBI, PLEKHO1, SEMA4D, and EPB41 vary, the proteins for all five of these genes are implicated in intracellular pathways (eg, Wnt, TGF‐β, PI3K‐AKT, and Hippo) as well as cellular functions including control of cell shape, cell migration, response to hypoxia, regulation of cell viability, differentiation and production of ECM proteins 101‐110 . GNA13 (G Protein Subunit Alpha 13) is a member of the guanine nucleotide‐binding protein family and is known to be involved in numerous transmembrane signaling pathways including RhoA/ROCK signaling (Uniprot) as well as Wnt and Hippo pathways, 111,112 upstream of cellular processes including cell shape, actomyosin‐contractility, migration, and cytoskeletal remodeling 112,113 .…”

“…While the expression profiles of the genes GNA13, BAMBI, PLEKHO1, SEMA4D, and EPB41 vary, the proteins for all five of these genes are implicated in intracellular pathways (eg, Wnt, TGF-β, PI3K-AKT, and Hippo) as well as cellular functions including control of cell shape, cell migration, response to hypoxia, regulation of cell viability, differentiation and production of ECM proteins. [101][102][103][104][105][106][107][108][109][110] functioning of membrane proteins and cell adhesion molecules. [114][115][116] Differences observed in expression of these genes are illustrative of the complex regulation used by cells to sense and respond to their mechanical and biochemical environment.…”

Differential Effect of Cobalt and Chromium Ions as Well as CoCr Particles on the Expression of Osteogenic Markers and Osteoblast Function

“…One possible explanation for this effect might be that CoCl 2 initiates HIF-1α signaling [ 34 ]. HIF-1α has been shown to regulate fibrotic tissue changes by inducing collagen expression, as well as TGF-β signaling [ 35 , 36 ].…”

Hypoxia, partial EMT and collective migration: Emerging culprits in metastasis

“…Exposure of MDA-MB-468 and T47D breast cancer cell line to hypoxia-induced Snail expression without affecting E -Cadherin levels consolidates the proposed connection between partial EMT and hypoxia [ 246 ]. Finally, the periodic stabilization and degradation of HIF-1α during hypoxia and re-oxygenation of cyclic hypoxia, respectively might result into periodic TGFβ signaling through BAMBI, a glycoprotein related to type I TGFβ receptor, which has been shown to be regulated by HIF-1α under hypoxic condition [ 247 ]. This, in turn, may promote hybrid E/M state, because long-term EMT inducing signal has shown to inhibit the recovery of cells back to epithelial state [ 171 ].…”