Evangelos Kolettas
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.
Chavdoula E, Habiel DM, Roupakia E, Markopoulos GS, Vasilaki E, Kokkalis A, Polyzos AP, Boleti H, Thanos D, Klinakis A, Kolettas E, Marcu KB. (2019). CHUK/IKKa loss in lung epithelial cells enhances non-small cell lung cancer (NSCLC) growth associated with HIF up-regulation. Life Sci Alliance. 2:e201900460.
Markopoulos GS, Roupakia E, Tokamani M, Chavdoula E, Hatziapostolou M, Polytarchou C, Marcu KB, Papavassiliou AG, Sandaltzopoulos R, Kolettas E. (2017). A step-by-step microRNA guide to cancer development and metastasis. Cell Oncol (Dordr). 40:303-339.
Sfikas A, Batsi C, Tselikou E, Vartholomatos G, Monokrousos N, Pappas P, Christoforidis S, Tzavaras T, Kanavaros P, Gorgoulis VG, Marcu KB, Kolettas E. (2012). The canonical NF-κB pathway differentially protects normal and human tumour cells from ROS-induced DNA damage. Cell Signal. 24:2007-23.
Sideridou M, Zakopoulou R, Evangelou K, Liontos M, Kotsinas A, Rampakakis E, Gagos S, Kahata K, Grabusic K, Gkouskou K, Trougakos IP, Kolettas E, Georgakilas AG, Volarevic S, Eliopoulos AG, Zannis-Hadjopoulos M, Moustakas A, Gorgoulis VG. (2011). Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins. J Cell Biol. 195:1123-40.
Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC, Takaoka M, Nakagawa H, Tort F, Fugger K, Johansson F, Sehested M, Andersen CL, Dyrskjot L, Ørntoft T, Lukas J, Kittas C, Helleday T, Halazonetis TD, Bartek J, Gorgoulis VG. (2006). Oncogene-induced senescence is part of the tumourigenesis barrier imposed by DNA damage checkpoints. Nature. 444:633-7.
Roupakia E, Markopoulos GS, Kolettas E. (2021). Genes and pathways involved in senescence bypass identified by functional genetic screens. Mech. Ageing. Dev. Jan 8; 194:111432
Ntellas P, Mavroeidis L, Gkoura S, Gazouli I, Amylidou A-L, Papadaki A, Zarkavelis G, Mauri D, Karpathiou G, Kolettas E, Batistatou A and Pentheroudakis G. (2020). Old player-new tricks: Non angiogenic effects of the VEGF/VEGFR pathway in cancer. Cancers (Basel) 12(11):E3145
Markopoulos G, Roupakia E, Marcu KB and Kolettas E. (2019). Epigenetic regulation of inflammatory cytokine-induced epithelial-to-mesenchymal cell transition and in the generation of cancer stem cells. Cells 8(10), Sep 25, pii: E1143
Markopoulos G, Roupakia E, Tokamani M, Alabasi G, Sandaltzopoulos R, Marcu KB, Kolettas E. (2018). Roles of NF-κB signalling in the regulation of miRNAs impacting on inflammation in cancer. Biomedicines 6(2):40, 198-216
Roupakia E, Markopoulos G and Kolettas E. (2018). IL-12-mediated transcriptional regulation of matrix metalloproteinases. Bioscience Rep. 38(3) BSR20171420.
Patounas O, Papacharalampous I, Eckerich C, Markopoulos G, Kolettas E and Fackelmayer FO. (2018). A novel splicing isoform of Protein Arginine Methyltransferase 1 (PRMT1) that lacks the dimerization arm and correlates with cellular malignancy. J. Cell. Biochem. 119(2):2110-2123.
Markopoulos G, Roupakia E, Tokamani M, Vartholomatos G, Tzavaras T, Hatziapostolou M, Fackelmayer FO, Sandaltzopoulos R, Polytarchou C, Kolettas E. (2017). Senescence-associated microRNAs target cell cycle regulation genes in human lung fibroblasts. Exp. Gerontol. 96:110-22
Sigala F, Savvari P, Liontos M, Sigalas P, Pateras IS, Papalampros A, Basdra E, Kolettas E, Kotsinas A, Papavassiliou AG and Gorgoulis VG. (2010). Increased expression of bFGF is associated with carotid atheromatic plaques instability engaging the NF-κB pathway. J. Cell. Mol. Med. 14:2273-2280.
Batsi C, Markopoulou S, Kontargiris E, Charalambous Ch, Thomas Ch, Christoforidis S, Kanavaros P, Constantinou AI, Marcu KB, Kolettas E. (2009). Bcl-2 blocks 2-methoxyestradiol induced leukaemia cell apoptosis by a p27Kip1 dependent G1/S cell cycle arrest in conjunction with NF-κB activation. Biochem. Pharmacol. 78:33-44.
Batsi C, Markopoulou S, Vartholomatos G, Georgiou I, Kanavaros P, Gorgoulis VG, Marcu KB, Kolettas E. (2009). Chronic NF-κB activation delays RasV12-induced premature senescence of human fibroblasts by suppressing the DNA damage checkpoint response. Mech. Ageing Dev. 13:409-419.
Markopoulou S, Kontargiris E, Batsi C, Tzavaras T, Trougakos IP, Boothman DA, Gonos ES and Kolettas E. (2009). Vanadium-induced apoptosis of HaCaT cells is mediated by c-fos and involves nuclear accumulation of clusterin. FEBS J. 276:4208-4223.
Barradas M, Gonos ES, Zebedee Z, Kolettas E, Petropoulou C, Delgado MD, Leon J, Hara E and Serrano M. (2002). Identification of a candidate tumour suppressor gene specifically activated during ras-induced senescence. Exp. Cell Res. 173(2):127-137.
Petropoulou C, Trougakos I, Kolettas E, Toussaint O and Gonos ES. (2001). Clusterin / Apolipoprotein J is a novel biomarker of cellular senescence that does not affect the proliferative capacity of human diploid fibroblasts. FEBS Lett. 509:287-297.
Rosenberger RF, Gounaris EG, Kolettas E. (1991). Mechanisms responsible for the limited and immortal phenotype in cultured mammalian cells. J. Theor. Biol. 148:383-392