Table 2.
In vivo evidence of the causal roles of genetic alterations of the TRAF family in cancer pathogenesis.
| Mouse models | Cancer-related phenotype | References |
|---|---|---|
| TRAF1 | ||
| TRAF1−/− | Increased skin sensitivity to TNFα-induced necrosis | (29) |
| Reduced skin tumors induced by DMBA/solar UVR due to defective UVR-induced | (20) | |
| ERK5 phosphorylation Reduced lung tumors induced by urethane i.p. administration due to increased |
(30) | |
| TRAF2-mediated ubiquitination and degradation of BRAF | ||
| Enhanced T cell proliferation in response to TCR-NF-κB1 signaling | (29, 31) | |
| Impaired CD8 and memory T cell survival in response to 4-1BB-NF-κB2 signaling | (31–33, 34) | |
| TRAF1-tg | Decreased antigen-induced apoptosis of CD8 T lymphocytes | (35) |
| p80HT tg/TRAF1−/− | Reduced development of small lymphocytic lymphoma | (27) |
| TRAF2 | ||
| TRAF2−/− | Early lethality, reduced TNFα-mediated JNK activation | (36) |
| Spontaneous severe colitis and TNFα-dependent apoptosis of colonic epithelial cells | (37) | |
| Decreased viability of skeletal muscle tissue due to impaired TNFα-induced NF-κB activation in myotubes | (38) | |
| B cell KO: TRAF3flox/flox, CD19-Cre | Prolonged B cell survival, splenomegaly and lymphadenopathy due to constitutive NF-κB2 activation, but defective CD40-induced NF-κB1 activation and proliferation | (39) |
| B cell tg: Igh-TRAF2DN (ΔN240aa) tg | Lymphadenopathy and splenomegaly due to increased number of B cells | (40, 41) |
| Igh-TRAF2DN (ΔN240aa)/Bcl-2 tg | Spontaneously development of small lymphocytic lymphoma | (41, 42) |
| Liver parenchymal cell KO: TRAF2flox/flox, Ripk1flox/flox, Alfp-Cre | Spontaneous development of hepatocellular carcinoma due to extensive hepatocyte apoptosis, caspase 8 hyperactivation and impaired TNFα-induced NF-κB activation | (43) |
| Induced KO: TRAF2flox/flox, Rosa-creERT2 | Rapid lethality that is dependent on Ripk3, TNFR1, DR5 and Fas signaling and increased hepatic necroptosome assembly and necroptosis | (44) |
| Keratinocyte KO: TRAF2flox/flox, K14-Cre | Psoriatic skin inflammation and epidermal hyperplasia that is partially dependent on TNFα, constitutive NF-κB2 activation and inflammatory cytokine expression | (45) |
| Myeloid cell KO: TRAF2flox/flox, LysM-Cre | Exacerbated DSS-induced colitis due to increased TLR-induced inflammatory cytokine production caused by elevated c-Rel and IRF5 protein levels in macrophages | (46) |
| T cell KO: TRAF2flox/flox, Lck-Cre | Decreased NKT cells and CD8 naïve and memory T cells due to impaired IL-15 signaling in NKT cells and defective IL-15-induced proliferation of CD8 T cells | (47) |
| TRAF3 | ||
| TRAF3−/− | Early lethality, which could be resued by compound loss of p100 NF-κB2 or NIK | (48–50) |
| Defective antigen-induced T cell proliferation | (49) | |
| B cell KO: TRAF3flox/flox, CD19-Cre | Expanded B cell compartment, splenomegaly and lymphadenopathy due to prolonged B cell survival caused by constitutive NF-κB2 activation | (539, 51) |
| Spontaneous development of splenic marginal zone lymphoma and B1 lymphoma | (52) | |
| Enhanced signaling by TLR3, TLR4, TLR7, and TLR9 in B cells | (53) | |
| Accelerated CD40-induced phosphorylation of JNK, p38, and ERK | (54) | |
| B cell Tg: Igh-TRAF3 Tg | Spontaneous plasmacytosis, autoimmunity, inflammation and cancer, particularly squamous cell carcinomas of the tongue and salivary gland tumors | (55) |
| Myeloid cell KO: TRAF3flox/flox, LysM-Cre | Spontaneous development of histiocytic sarcoma, B lymphoma, liver cancer, or chronic inflammation that often affect multiple organs in aging mice | (56) |
| Exacerbated DSS-induced colitis due to increased TLR-induced inflammatory cytokine production caused by elevated c-Rel and IRF5 protein levels in macrophages | (46) | |
| T cell KO: TRAF3flox/flox, CD4-Cre | Impaired T cell proliferation in response to co-engagement of TCR and CD28 | (57) |
| Increased number of Treg cells due to enhanced IL-2 signaling | (57, 58) | |
| Impaired IL-15-induced iNKT cell proliferation and survival | (59) | |
| Reduced number of CD8 central memory T cells due to impaired IL-15 signaling | (60) | |
| TRAF4 | ||
| TRAF4−/− | Defects in embryonic development and neurulation | (61–63) |
| Reduced migration of DCs | (64) | |
| Reduced skin tumors induced by DMBA/TPA due to diminished IL-17A–induced ERK5 activation and epidermal hyperplasia | (65) | |
| Blunted airway inflammation and Th2 cytokine production in response to IL-25 administration due to defective IL-25R-Act1 signaling | (66) | |
| TRAF5 | ||
| TRAF5−/− | Defective CD40-induced proliferation and surface molecule upregulation in B cells | (67) |
| Decreased CD40 plus IL-4-induced Ig production in B cells | (67) | |
| Impaired CD27-induced survival and proliferation in CD4 and CD8 T cells | (67, 68) | |
| Defective GITR-induced proliferation, IL-2 production and NF-κB/p38/ERK1/2 activation in CD4 T cells | (69) | |
| Enhanced OX40-induced Th2 differentiation of CD4 T cells and exacerbated Th2-driven lung inflammation | (70) | |
| Enhanced IL-6-induced CD4 Th17 differentiation due to increased IL-6-gp130-STAT3 signaling and exaggerated Th17-driven experimental autoimmune encephalomyelitis | (71) | |
| Exacerbated DSS-induced colitis and increased NF-κB activation in the colon | (72) | |
| CD40LMP1-tg/TRAF5−/− | Reduced spleen and LN size compared to CD40LMP1-tg mice, decreased serum IL-6 and autoantibodies, and decreased LMP1-mediated JNK activation in B cells. | (73) |
| TRAF6 | ||
| TRAF6−/− | Reduced number of immature B cells in the bone marrow | (74) |
| Defective differentiation of osteoclasts, DCs, and Treg cells | (74–77) | |
| Defective IL-1, CD40, LPS and RANK signaling | (74, 75) | |
| Loss of NF-κB activity in the epithelia and vasculature during development | (78) | |
| Impaired NGF-p75NTR-induced NF-κB activation and survival in Schwann cells | (79) | |
| Defective BDNF-p75NTR-induced JNK activation and apoptosis in neurons | (79, 80) | |
| Hematopoietic KO:TRAF6flox/flox, Vav-Cre | Decreased basal IKKβ-NF-κB activation, impaired hematopoietic stem cell self-renewal and loss of hematopoietic stem/progenitor cells (HSPCs) | (81) |
| B cell KO: TRAF6flox/flox, CD19-Cre | Reduced number of mature B cells in the bone marrow and spleen, defective development of B1 B cells, and defective CD40 and TLR signaling in B cells | (82) |
| T cell KO: TRAF6flox/flox, CD4-Cre | Multiorgan inflammation and hyperactivation of TCR-PI3K-Akt signaling in CD4 T cells | (83) |
| Defects in generating CD8 memory T cells due to impaired AMPK-activation and mitochondrial fatty acid oxidation in response to growth factor withdrawal | (84) | |
| Increased Th17 differentiation due to increased sensitivity of CD4 T cells to TGFβ-induced Smad2/3 activation and proliferation arrest | (85) | |
| Impaired OX40-induced Th9 differentiation due to defective OX40-NIK-NF-κB2 signaling | (86) | |
| Intestinal epithelial cell KO: TRAF6flox/flox, Villin-Cre | Exacerbated DSS-induced colitis due to altered gut microbiota, which is independent of TLR signaling in intestinal epithelial cells | (87) |
| Skeletal muscle KO:TRAF6flox/flox, MCK-Cre | Minimal muscle loss in response to transplanted tumor growth due to defective activation of NF-κB, ubiquitin-proteasome and autophagy-lysosomal systems | (88) |
| Improved regeneration of myofibers upon injury due to upregulated Notch signaling but downregulated NF-κB activation and inflammatory cytokine production | (89) | |
| Reduced starvation-induced skeletal muscle atrophy due to increased phosphorylation of Akt and FoxO3a and decreased AMPK activation | (90) | |
Direct evidence in tumorigenesis is highlighted in blue font.