The Death Domain Kinase RIP Mediates the TNF-Induced NF-κB Signal

The death domain serine/threonine kinase RIP interacts with the death receptors Fas and tumor necrosis receptor 1 (TNFR1). In vitro, RIP stimulates apoptosis, SAPK/JNK, and NF-kappaB activation. To define the physiologic role(s) that RIP plays in regulating apoptosis in vivo, we introduced a rip null mutation in mice through homologous recombination. RIP-deficient mice appear normal at birth but fail to thrive, displaying extensive apoptosis in both the lymphoid and adipose tissue and dying at 1-3 days of age. In contrast to a normal thymic anti-Fas response, rip-/- cells are highly sensitive to TNFalpha-induced cell death. Sensitivity to TNFalpha-mediated cell death in rip-/- cells is accompanied by a failure to activate the transcription factor NF-kappaB.

[1]  S. Grimm,et al.  Bcl-2 down-regulates the activity of transcription factor NF-kappaB induced upon apoptosis , 1996, The Journal of cell biology.

[2]  A. Baldwin,et al.  THE NF-κB AND IκB PROTEINS: New Discoveries and Insights , 1996 .

[3]  S. Nagata,et al.  Apoptosis by Death Factor , 1997, Cell.

[4]  R. Flavell,et al.  Distinct Roles in Lymphoid Organogenesis for Lymphotoxins α and β Revealed in Lymphotoxin β–Deficient Mice , 1997 .

[5]  A. Chinnaiyan,et al.  Signal Transduction by DR3, a Death Domain-Containing Receptor Related to TNFR-1 and CD95 , 1996, Science.

[6]  E. Chen,et al.  Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[7]  D. Wallach,et al.  MAP3K-related kinase involved in NF-KB induction by TNF, CD95 and IL-1 , 1997, Nature.

[8]  B. Seed,et al.  RIP mediates tumor necrosis factor receptor 1 activation of NF‐kappaB but not Fas/APO‐1‐initiated apoptosis. , 1996, The EMBO journal.

[9]  D. Goeddel,et al.  The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation , 1995, Cell.

[10]  E. Zandi,et al.  The IκB Kinase Complex (IKK) Contains Two Kinase Subunits, IKKα and IKKβ, Necessary for IκB Phosphorylation and NF-κB Activation , 1997, Cell.

[11]  P. Baeuerle,et al.  Function and activation of NF-kappa B in the immune system. , 1994, Annual review of immunology.

[12]  Marty W. Mayo,et al.  TNF- and Cancer Therapy-Induced Apoptosis: Potentiation by Inhibition of NF-κB , 1996, Science.

[13]  Seamus J. Martin,et al.  Suppression of TNF-α-Induced Apoptosis by NF-κB , 1996, Science.

[14]  D. Goeddel,et al.  TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. , 1996, Immunity.

[15]  Michael Karin,et al.  Dissection of TNF Receptor 1 Effector Functions: JNK Activation Is Not Linked to Apoptosis While NF-κB Activation Prevents Cell Death , 1996, Cell.

[16]  D. Goeddel,et al.  A death-domain-containing receptor that mediates apoptosis , 1996, Nature.

[17]  Mike Rothe,et al.  Tumor necrosis factor's cytotoxic activity is signaled by the p55 TNF receptor , 1993, Cell.

[18]  D. Goeddel,et al.  Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice , 1994, Nature.

[19]  E M Schwarz,et al.  Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. , 1995, Genes & development.

[20]  D. Baltimore,et al.  I kappa B: a specific inhibitor of the NF-kappa B transcription factor. , 1988, Science.

[21]  Stephen J. Elledge,et al.  Mice Lacking p21 CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control , 1995, Cell.

[22]  Mike Rothe,et al.  IκB Kinase-β: NF-κB Activation and Complex Formation with IκB Kinase-α and NIK , 1997 .

[23]  Hong-Bing Shu,et al.  TRADD–TRAF2 and TRADD–FADD Interactions Define Two Distinct TNF Receptor 1 Signal Transduction Pathways , 1996, Cell.

[24]  David M. Rothwarf,et al.  A cytokine-responsive IκB kinase that activates the transcription factor NF-κB , 1997, Nature.

[25]  P. Leder,et al.  RIP and FADD: two "death domain"-containing proteins can induce apoptosis by convergent, but dissociable, pathways. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Vishva M. Dixit,et al.  RAIDD is a new 'death' adaptor molecule , 1997, Nature.

[27]  Scott F. Smith,et al.  Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. , 1994, Science.

[28]  R. Bronson,et al.  Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene , 1991, Cell.

[29]  K. Bauer,et al.  Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-κB , 1996, Current Biology.

[30]  Matthias Mann,et al.  FLICE, A Novel FADD-Homologous ICE/CED-3–like Protease, Is Recruited to the CD95 (Fas/APO-1) Death-Inducing Signaling Complex , 1996, Cell.

[31]  D. Goeddel,et al.  Identification and Characterization of an IκB Kinase , 1997, Cell.

[32]  D. Baltimore,et al.  Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses. , 1996, Immunity.

[33]  P. Leder,et al.  RIP: A novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death , 1995, Cell.

[34]  T. Mak,et al.  Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection , 1993, Cell.

[35]  Matthias Mann,et al.  IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB Activation , 1997 .

[36]  A. Baldwin,et al.  The I kappa B proteins: multifunctional regulators of Rel/NF-kappa B transcription factors. , 1993, Genes & development.

[37]  R. Zinkernagel,et al.  Mice lacking the tumour necrosis factor receptor 1 are resistant to IMF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes , 1993, Nature.

[38]  B. Dérijard,et al.  Transcription factor ATF2 regulation by the JNK signal transduction pathway , 1995, Science.

[39]  Arul M. Chinnaiyan,et al.  FADD, a novel death domain-containing protein, interacts with the death domain of fas and initiates apoptosis , 1995, Cell.

[40]  P. Leder,et al.  Tal‐1 induces T cell acute lymphoblastic leukemia accelerated by casein kinase IIalpha. , 1996, The EMBO journal.

[41]  C. Ware,et al.  A lymphotoxin-beta-specific receptor. , 1994, Science.

[42]  D. Goeddel,et al.  Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. , 1997, Immunity.

[43]  David Baltimore,et al.  An Essential Role for NF-κB in Preventing TNF-α-Induced Cell Death , 1996, Science.