HIF1Alpha_Pathway之经典信号通路.ppt

HSP70 HIF1a Pathway Elongin-B Elongin-C Elongin-B p53 MKK3 MKK6 ERK2 FIH1 Ref1 PHD2 PHD1 TCP1a HSP90 MDM2 Ub HIF1a HIF1a HIF1a HIF1a HIF1a HIF1a Per1 JAB1 Ub Ub Ub Ub Ub VHL VHL ARNT HNF4a2 SRC1 HIF1a Degradation HIF1a ARNT CREB c-Jun Cul2 RBX1 PSM-a7 Proteasome LDHA ATP ET1 Epo VEGF NOSIII Glucose Transporter Glucose Transporter Glucose Cytoplasmic Storage Vesicle Glucose Transporters Hypoxia Normoxia Pyruvate Glucose Asparagine Hydroxylase OH Gene Expression HRE VEGF Pathway NOS Pathway p53 Hypoxia Pathway p300 CBP P P P P OH VHL Elongin-C p16(INK4A) Glucose 2009 ProteinL C * Review: The cellular response to O2 (oxygen) is a central process in animal cells and figures prominently in the pathophysiology of several diseases, including cancer, cardiovascular disease, and stroke. This process is coordinated by the HIF (Hypoxia-Inducible Factor) and its regulator, the pVHL (Von Hippel-Lindau tumor suppressor protein). HIF1 is a basic helix-loop-helix transcription factor that transactivates genes encoding proteins that participate in homeostatic responses to hypoxia. It induces expression of proteins controlling glucose metabolism, cell proliferation, and vascularization. Several genes involved in cellular differentiation are directly or indirectly regulated by hypoxia. These include Epo (Erythropoietin), LDHA (Lactate Dehydrogenase-A), ET1 (Endothelin-1), transferrin, transferrin receptor, VEGF (Vascular Endothelial Growth Factor), Flk1, FLT1 (Fms-Related Tyrosine Kinase-1), PDGF-Beta (Platelet-Derived Growth Factor-Beta), bFGF (basic Fibroblast Growth Factor), and others genes affecting glycolysis (Ref.1). HIF1 consists of a heterodimer of two basic helix-loop-helix PAS (Per-ARNT-Sim) proteins, HIF1-Alpha, and HIF1-Beta. HIF1-Alpha accumulates under hypoxic conditions whereas HIF1-Beta is constitutively expressed. HIF1-Alpha is an important mediator of the hypoxic response of tumor cells and controls the up-regulation of a number of factors important for soli