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HEMATOLOGICAL MALIGNANCIES SOLID TUMORS 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 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 Figure 1 : Human cancers that have been linked to constitutive NF-B activation Inflammation Proliferation TNF, IL1, IL8, MIP-2, MCP-1, iNOS, COX2, ICAM-1, E-Selectin CyclinD1, CyclinE, CDK2, c-MYC, TNF, IL1, IL6 Survival Cell death and anti-proliferative effects NF-B FasL, Fas and DR4/5 p53 p21WAF1/CIP1 Angiogenesis CXCL-1/8, IL-1/6, VEGF, IL8, HIF-1, TNF 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 Figure 2: NF-B target genes involved in cancer development and progression Classical NF-B Pathway CD40L BAFF CD40L BAFF TRAF5/6 c-IAP1 Alternative NF-B Pathway TRAF5/6 TRAF2 TRAF2 c-IAP1 TRAF3 c-IAP2 c-IAP2 NIK CYLD TAK1 IKK MLN IKK IKK IKK IKK BTZMB RelA p105 RelA P P IB RelB p100 p50 P P P P RelB p100 p50 BTZMB p100 processing p105 processing Proteosomal degradation RelA p50 RelA p50 Innate immunity Inflammation Cell survival Target genes RelB p52 RelB p50 RelB p50 RelB p52 Target genes Lymphoid organogenesis B-cell maturation Humoral immunity Figure 3 : NF-B gain- and loss-of-function mutations in multiple myeloma TNF- IAP antagonists FADD Caspase-8 c-IAP1 TRAF2 Ub TRAF2 c-IAP2 TRAF3 TRAF2 Ub c-IAP1 Ub Ub Ub Ub c-IAP2 Ub IAP antagonists Proteosomal degradation IKK Caspase-3 XIAP IKK IKK P P RelB IKK IKK p100 Proteosomal degradation c-IAP2 NIK Proteosomal degradation c-IAP1 Ub RIP1 P P Caspase-7 RelA RelB p100 P P IB p50 p50 p100 processing Apoptosis Proteosomal degradation Proteosomal degradation RelB p50 RelB p50 RelB p52 RelA p50 RelA p50 RelB p52 Target genes Apoptosis Target genes Bcl-xL c-IAP1/2 TRAF1/2 Bcl-2 A20 XIAP c-FLIP c-FLIP TNF- Figure 4: cIAPs and IAP antagonists in the regulation of NF-B and cell death pathways
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