NF- B

1. HEMATOLOGICAL MALIGNANCIES SOLID TUMORS Breast Cancer Cervical Cancer Prostate Cancer Renal Cancer Lung Cancer Colon Cancer Liver Cancer Pancreatic Cancer Esophageal Cancer Gastric Cancer Laryngeal Cancer Thyroid Cancer Parathyroid Cancer Melanoma Bladder Cancer Cylindroma Squamous Cell Carcinoma (Skin) Squamous Cell Carcinoma (Head and Neck) Oral Carcinoma Endometrial Carcinoma Ovarian Cancer Retinoblastoma Astrocytoma/Glioblastoma Multiple Myeloma Mantle Cell Lymphoma MALT Lymphoma Diffuse Large B-cell Lymphoma Hodgkin’s Lymphoma Myelodysplasic Syndrome Adult T-cell Leukemia (HTLV-1) Acute Lymphocytic Leukemia Acute Myeloid Leukemia Chronic Lymphocytic Leukemia Chronic Myeloid Leukemia NF-B Figure 1 : Human cancers that have been linked to constitutive NF-B activation

2. Proliferation CyclinD1, CyclinE, CDK2, c-MYC, TNF, IL1, IL6 Inflammation TNF, IL1, IL8, MIP-2, MCP-1, iNOS, COX2, ICAM-1, E-Selectin Cell death and anti-proliferative effects FasL, Fas and DR4/5 p53 p21WAF1/CIP1 NF-B Survival A1/BFL1, GADD45, Bcl-2, Bcl-XL, TRAF1/2, XIAP, cIAP1/2, c-FLIP, A20, IEX-1L, Survivin, Telomerase, MnSOD Tumor promotion and Metastasis uPA, MMP2/9, VCAM-1, ICAM-1, ELAM-1, Kal-1, COX2, iNOS Angiogenesis CXCL-1/8, IL-1/6, VEGF, IL8, HIF-1, TNF Figure 2: NF-B target genes involved in cancer development and progression

3. IKK IKK IKK IKK IKK p105 processing Proteosomal degradation p52 p52 RelB RelB p50 p50 RelB RelB p50 p50 RelA RelA CD40L BAFF CD40L BAFF Classical NF-B Pathway Alternative NF-B Pathway TRAF5/6 TRAF5/6 TRAF2 TRAF2 c-IAP1 c-IAP1 TRAF3 c-IAP2 c-IAP2 NIK MLN TAK1 CYLD BTZMB P P P P RelA RelB RelB p100 p100 RelA p50 p105 P p50 IB BTZMB P p100 processing Innate immunity Inflammation Cell survival Lymphoid organogenesis B-cell maturation Humoral immunity Target genes Target genes Figure 3 : NF-B gain- and loss-of-function mutations in multiple myeloma

4. Proteosomal degradation c-IAP1 c-IAP1 c-IAP1 Proteosomal degradation c-IAP2 c-IAP2 c-IAP2 TRADD IKK IKK IKK IKK IKK RelA P P p100 p50 P IB P p100 processing Proteosomal degradation Proteosomal degradation Proteosomal degradation p52 p52 RelB RelB p50 p50 RelB RelB p50 RelA A20 Bcl-xL Bcl-2 Target genes c-FLIP XIAP c-IAP1/2 TRAF1/2 c-FLIP TNF- IAP antagonists Caspase-8 FADD TRAF2 TRAF2 Ub Ub RIP1 Ub Ub TRAF3 TRAF2 Ub Ub NIK Ub IAP antagonists Ub Caspase-3 XIAP Caspase-7 P P RelB RelB p100 p50 Apoptosis RelA p50 Target genes TNF- Apoptosis Figure 4: cIAPs and IAP antagonists in the regulation of NF-B and cell death pathways