Regulatory mechanism of hypoxia-inducible factor (HIF-1) expression. Growth factor stimulation induces HIF-1α subunit (HIF-1α) protein synthesis by activating PI3K/Akt/mTOR and Ras/MEK/ERK kinase pathways. Under normoxic conditions, HIF-1α is hydroxylated by proline hydroxylases (PHDs), triggering its interaction between von Hippel-Lindau tumor suppressor protein (pVHL), leading to its polyubiquitination and subsequent proteasomal degradation. In contrast, under hypoxic conditions, HIF-1α remains stable, enters the nucleus, and, together with HIF-1β, binds to hypoxia-responsive elements (HREs), upregulating the expression of target genes such as glucose transporters (GLUTs), vascular endothelial growth factors (VEGFs), and matrix metalloproteinases (MMPs). Ub: ubiquitin.