Figure 5.

Multi-level regulation of vitamin D and integrated pathways with Ras-signalling controlled by neurofibromin. When 1,25(OH)₂D binds VDRs present at the cell membrane, vitamin D influences different metabolic signalling molecules. Vitamin D inhibits the expression of both EGF and VEGF cytokines, as well as the Ras-signalling, while induces the activity of AMPK, which in turn, inhibits mTOR action. Conversely, upon binding to cytosolic VDRs, a trimeric complex with RXRs is formed, which then translocates in the nucleus and binds VDREs, finally regulating gene expression, including the transcription of VDUP1/TXNIP mRNA. In turn, VDUP1/TXNIP exerts several activities (L.P. is currently working on novel molecular pathways regulated from TXNIP): 1) enhancement of ROS with consequent extreme oxidative stress and cell death; 2) increase of activity of p27^kip1, which inhibits G1/S cell cycle transition. Due to the action of TXNIP, p27kip1 is stabilised and retained in the nucleus where it exerts its inhibitory activity on the proliferation of malignant cells; 3) promotion of the active reduced form of PTEN, which inhibits the PI3K/ATK/mTOR signalling cascade. Vitamin D is also able to stimulate PTEN expression itself. On the other hand, neurofibromin promoting the inactive Ras-GDP form, completely inhibiting all the downstream effectors of the Ras-signalling cascade. RTKs: receptor tyrosine kinases; VDRs: vitamin D receptors; RXRs: retinoic acid X receptors; VDREs: vitamin D response elements; 1,25D-MARRS: 1,25D-membrane-associated, rapid response steroid-binding protein; EGF: endothelial growth factor; VEGF: vascular endothelial growth factor; AMPK: AMP-activated protein kinase; VDUP1: Vitamin D Up-regulated Protein 1; TXNIP: Thioredoxin Interacting Protein; PTEN: phosphatase and tensin homolog; ROS. reactive oxygen species.