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FADD/RIP1/RIP3 coregulation of apoptotic, necrotic and survival pathways in embryogenesis and lymphoid homeostasis
Author(s) -
Zhang Jianke
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.798.29
Subject(s) - fadd , necroptosis , microbiology and biotechnology , programmed cell death , ripk1 , biology , caspase 8 , apoptosis , tradd , death domain , embryonic stem cell , signal transduction , caspase , cancer research , biochemistry , gene
Programmed cell death including apoptosis and necrosis are fundamental biological processes that play essential roles during embryonic development and postnatal homeostasis in various tissues. The extrinsic apoptotic pathways induced through death receptors (DRs) require FADD to recruit and activate the apical caspase 8. Inactivation of each DR has no effect on embryogenesis. In contrast, FADD−/− mice die at mid‐gestation stages. The molecular mechanism underlying the paradoxical functions of FADD has been a long‐standing puzzle. Our recent data indicate that FADD regulates necroptosis, a RIP1‐dependent, necrosis‐like death pathway. RIP1, a serine/threonine kinase, is also involved in NF‐kB activation for survival. We demonstrated that RIP1 deficiency fully restored normal embryogenesis in FADD−/− mice. However, loss of FADD does not prevent neonatal lethality of RIP1−/− mice. The RIP1 homologue, RIP3, is also required for DR‐induced necrosis but dispensable for NF‐kB activation. RIP3 deficiency allows normal mouse development. We recently crossed RIP3 null alleles into FADD−/− mice. Our data indicate that FADD, RIP1 and RIP3 functions in concert to regulate two cell death pathways, apoptosis and necrosis, as well as survival pathways. Further analysis was performed to help reveal insights of the regulation including the function of additional regulatory proteins.