NF-kB & p53 Signalling Pathways in Health and Disease PDF

NF-κB & p53 signalling pathways in health and disease Dr Alessio Iannetti BMS2002 / L17 [email protected] Learning outcomes To describe the NF-kB and p53 signalling pathways To outline structure and functions of the NF-kB and p53 trans...

NF-κB & p53 signalling pathways in health and disease Dr Alessio Iannetti BMS2002 / L17 [email protected] Learning outcomes To describe the NF-kB and p53 signalling pathways To outline structure and functions of the NF-kB and p53 transcription factors To explain the roles of NF-kB and p53 in cancer and Rheumatoid Arthritis To understand the importance of NF-kB-p53 cross-talks in health and disease  NF-kB signalling and roles in cancer  Join the Vevox session Go to vevox.app Enter the session ID: 129-144-946 Or scan the QR code  NF-kB functions e.g. Physical DNA damage Infection Hypoxia stress Environmental challenges e.g. e.g. TNF receptor Sensor IB kinase complex Signalling pathway NF-B transcription factors Effector e.g. Gene Repair Programmed Immune Expression death response Cellular Response NF-B signalling pathways NIK Naugler et al (2008)  The Mammalian NF-kB Family RelA TA2 TA1 551 p105 Rel Homology Domain A A A A A A A DD Rel Homology Domain N N N N N N N (p65) (NF-kB1) K K K K K K K 969 RelB LZ Rel Homology Domain TAD 557 p50 Rel Homology Domain (NF-kB1) c-Rel Rel Homology Domain SD I SD II 619 A A A A A A A p100 Rel Homology Domain N N N N N N N DD 900 K K K K K K K (NF-kB2) p52 Rel Homology Domain (NF-kB2) - The Rel Homology Domain (RHD) encodes the DNA binding and dimerisation functions of NF-B - p50 and p52 are proteolytically processed from their precursor proteins p105 and p100 - p100 and p105 contain ankyrin repeats in their C-termini that allow them to function as IB inhibitors - TA1/TA2, TAD, SD1, SDII – non conserved transcriptional activation domains. 8 NF-kB NF-kB 9  Cancer-associated inducers of aberrant NF-B activity Genetic Oncogene alteration activation (subunit expression, (Ras, Bcr-Abl) IB deletion, regulators) Carcinogens Stress ROI inducers Tumour promoters (hypoxia) (PMA, UV) Cytokines Cancer therapies Infection (chemotherapeutic agents Microflora -irradiation) IKK NF-B Immortality Inflammation (telomerase) (IL-1, TNF, chemokines) Tumour promotion (COX2, iNOS, MMP-9, uPA) Angiogenesis (VEGF, TNF, IL-1, IL-8) Proliferation (Cyclin D1, c-Myc) Metastasis Survival (ICAM-1, VCAM-1, (Bcl-xL, XIAP, ELAM-1) cIAP1 & 2) Tumour promoting functions of aberrant NF-B activity  NF-B and cancer Tumours that Express Aberrantly Active NF-κB/Have Altered NF-κB/IκB proteins NF-B and diseases Q) With NF-B being involved in so many diseases and type of cancer why don’t we make a drug targeting this pathway as treatment for inflammatory diseases and cancer? A) Inhibiting NF-B may not always be a good idea……..  NF-κB under control NF-κB control lost Immune (mainly cytoplasmic) (aberrantly nuclear) Response Apoptosis Epithelial cell homeostasis Inflammation Normal cells Diseased cells NF-B/IKK inhibitor Unfortunately, due to its normal functions, inhibition of NF-B is not without adverse consequences.  A) Identifying new proteins under NF-kB transcriptional control could be the key… My main PhD publication My main Post-Doc publication 17  p53 signalling, its roles in cancer and cross- talks with NF-kB p53 functions p53 signalling pathways Taken from: MF Bellini et al, Journal of Biomedicine and Biotechnology, 2012  p53 structure HDM2 N-terminal domain contain a sub-transactivation domain and a proline rich domain which may be involved in regulation of apoptosis The core domain bind to specific DNA sequences The c-terminal domain contains the tetramerization domain and another DNA binding site within the regulatory region, associated with ssDNA, insertion, deletion DNA mismatches or Taken from Trends in damaged DNA Biochem Sciences 22 p53 p53 23 Both p53 and NF-B are activated by. similar stimuli. Therefore, mechanisms must exist to integrate their activities DNA-damage Stress Oncogene Activation Hdm2 RelA p50 p53 RelA p53 p50 ? Cell adhesion Cell Cycle Survival Apoptosis (Metastasis) Arrest (Bcl-xL, XIAP2, (Bax, PUMA, Proliferation (p21WAF1 IAP1 & 2 etc. PIG3 etc. Inflammation GADD45 Tumour Promoting Tumour Suppressing etc.) NF-B-p53 pathways are ‘tightly’ connected NF-B pathway p53 pathway NF-κB p53  The balance between NF-κB and p53 can control how cells respond to DNA damage Aberrant NF-κB Wild type p53 Normal NF-κB Mutant p53 27  NF-kB-p53 signalling in Rheumatoid Arthritis 4 Ways the NF-kB activation of immune cells contribute to RA Non-canonical Non-canonical Taken from Samimi et al, Autoimmunity Highlights 2020 4 Ways the NF-kB activation of signalling pathways in Fibroblasts-like Synoviocytes (FLS) can contribute to RA IL-1/IL-6/TNF Ser 536 RANKL CycD1 Taken from Samimi et al, Autoimmunity Pannus Highlights 2020  4 Ways p53 can control the homeostasis of immune cells DNT cells Taken from Taghadosi et al, Immunologic research 2021  4 Ways p53 can control inhibitory signalling in FLS IL-6 Taken from Taghadosi et al, Immunologic research 2021 FEEDBACK 33