The von Hippel–Lindau tumour suppressor interacts with microtubules through kinesin-2

AbstractSynthesis and maintenance of primary cilia are regulated by the von Hippel–Lindau (VHL) tumour suppressor protein. Recent studies indicate that this regulation is linked to microtubule-dependent functions of pVHL such as orienting microtubule growth and increasing plus-end microtubule stability, however little is known how this occurs. We have identified the kinesin-2 motor complex, known to regulate cilia, as a novel and endogenous pVHL binding partner. The interaction with kinesin-2 facilitates pVHL binding to microtubules. These data suggest that microtubule-dependent functions of pVHL are influenced by kinesin-2

Fibronectin is a hypoxia-independent target of the tumor suppressor VHL.

Item does not contain fulltextThe von Hippel-Lindau (VHL) tumor suppressor gene regulates the extracellular matrix by controlling fibronectin deposition. To identify novel VHL target genes, we subjected mRNA from VHL-deficient RCC cells (786-0-pRC) and a transfectant re-expressing wildtype VHL (786-0-VHL) to differential expression profiling. Among the differentially expressed genes, we detected that fibronectin is upregulated in the presence of VHL, while it is not affected by hypoxia. Thus regulation of fibronectin deposition by VHL occurs at the transcriptional level, irrespective of oxygen levels

Loss of Endogenous Bone Morphogenetic Protein-6 Aggravates Renal Fibrosis

Bone morphogenetic protein-6 (BMP-6) suppresses inflammatory genes in renal proximal tubular cells and regulates iron metabolism by inducing hepcidin. In diabetic patients, an increase of myofibroblast progenitor cells (MFPCs), also known as fibrocytes, was found to be associated with decreased BMP-6 expression. We hypothesized that loss of endogenous BMP-6 would aggravate renal injury and fibrosis. Wild type (WT) and BMP-6 null mice underwent unilateral ureteral obstruction. In WT mice, ureteral obstruction down-regulated BMP-6. Obstructed kidneys of BMP-6 null mice showed more casts (1.5-fold), epithelial necrosis (1.4-fold), and brush border loss (1.3-fold). This was associated with more inflammation (1.8-fold more CD45+ cells) and more pronounced overexpression of profibrotic genes for αSMA (2.0-fold), collagen I (6.8-fold), fibronectin (4.3-fold), CTGF (1.8-fold), and PAI-1 (3.8-fold), despite similar BMP-7 expression. Also, 1.3-fold more MFPCs were obtained from BMP-6 null than from WT mononuclear cell cultures, but in vivo only very few MFPCs were observed in obstructed kidneys, irrespective of BMP-6 genotype. The obstructed kidneys of BMP-6 null mice showed 2.2-fold more iron deposition, in association with 3.3-fold higher expression of the oxidative stress marker HO-1. Thus, ureteral obstruction leads to down-regulation of BMP-6 expression, and BMP-6 deficiency aggravates tubulointerstitial damage and fibrosis independent of BMP-7. This process appears to involve loss of both direct anti-inflammatory and antifibrotic action and indirect suppressive effects on renal iron deposition, oxidative stress, and MFPCs