NF-κB signalling pathways and IKK/NF-κB-miRNA regulatory network in DNA damage and inflammation impacting on senescence and cancer
NF-κB transcription factors (TFs) are critical regulators of pro-inflammatory/stress-like responses, and their immediate upstream signaling components are aberrantly expressed and/or activated in pulmonary diseases and in non-small cell lung cancer (NSCLC), with an unfavourable prognosis for patient survival. Activation of NF-κB is achieved by two main signalling pathways: An IKKβ-mediated canonical NF-κB signalling pathway involving the nuclear translocation of c-Rel/p50 or p65/50 heterodimes where they regulate target gene expression, and an IKKα-mediated non-canonical or alternative NF-κB signalling pathway involving the nuclear translocation of p52/RelB heterodimers to regulate a distinct set of NF-κB target gene expression.
Using in vitro cell systems and in vivo novel mouse lung cancer models, we study the:
1. Mechanisms of action of canonical IKKβ/NF-κB in NSCLC
2. Role of the regulatory NF-κB-miRNA network in NSCLC
3. Mechanism of action of IKKα in NSCLC
4. Mechanisms of action of IKKα in oncogene induced senescence
Identifying novel regulators of DNA damage, inflammation and cancer by employing domain-specific CRISPR/Cas9 screens
We will employ a functional kinase- or a transcription factor-specific CRISPR/Cas9 lentiviral library to ablate protein kinases or TFs and identify novel regulators involved in DNA damage and inflammation impacting on cancer.
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