研究生课 细胞凋亡的主要信号转导途径分子生物学课.ppt

Bax/Bcl-2 Bax Bcl-2 Bcl-2 Bcl-2 Bax Bax Survival Apoptosis Bcl-2 and Bax balance Bax/Bcl-2 Outer Mitochondrial Membrane Cyt. c Bax APAF-1 ProCASP 9 CASP 9 Cyt. c APOPTOSIS Bcl-2 Bcl-2 Bax act on cyto c release P53 - GUARDIAN OF THE GENOME p53 induces apoptosis, when expressed in very high levels - irreversible DNA damage cell has completed S-phase (DNA replicated) DNA Damage Damage Response p53 Arrest/Repair G1/S G2 Apoptosis via Bax Bax – target of p53 DNA Damage- induced apoptosis Role of p53 and Bax Another level of apoptotic regulation Pro-apoptotic when unphosphorylated Inhibits anti-apoptotic Bcl-2 family members Sensitizes the cell to apoptosis Inactive when phosphorylated (ex. by Akt1; 1999, Science) Bcl-2 Bcl-2 Bax Bax BAD BAD protein of the Bcl-2 family A model for the role of Bcl-2 family members in apoptosis. Apoptotic Pathways Effectors Modulators Caspase family Bcl-2 family Adaptors, FADD, TRADD Apaf-1, Smac Cytochrome c Endonuclease, DFF45, EndoG IAPs others Signalling pathways induced by CD95 Fas-associated Death Domain Death-inducing signaling complex IAP proteins (DIAP, XIAP, etc.) IAP inhibitors Reaper, Hid, Grim (fly) Smac, DIABLO (mammal) Signaling Factors Initiaion Regulator or modulators Execution or effectors Clearance Phagocyte ApoptoticCell RAC-1 DOCK 180 CRKII ELMO CytoskeletalReorganization forEngulfment C1q Receptor Bridge C1q C1qBindingSite PS Phosphatidyl-serineReceptors ScavengerReceptors ? Oxidized LDL-like Site Apoptosis and Phagocytosis Phagocytes recognize “eat-me” or cell corpse signals on the apoptotic cell surface. These signal the phagocyte to activate cellular engulfment machinery. Phosphatidylserine exposure on the target cell surface and the phosphatidylserine receptor on the phagocyte are essential for phagocytosis. Defining other receptors, bridge molecules, “eat-me” signals and signaling molecules involved in initiating the cytosolic changes needed for engulfment are very active areas of research. Th