DEFINING NOVEL MECHANISMS WHEREBY IKK DEPENDENT NF-KAPPAB ACTIVATION IMPACTS ON THE CONTROL OF E2F-TARGET GENES IN NORMAL AND CANCER CELLS

Abstract: 

Carcinogenesis involves the accumulation of mutations along with epigenetic changes leading to dominant alterations in gene expression and cell physiology. NFκB and E2F transcription factor pathways have important roles in cell growth control and viability and are deregulated in cancer. However, NFκB and E2F functions are quite distinct and can also antagonize each other. NFκBs generally promote cell proliferation and survival; but E2Fs can act as either transcriptional activators or suppressors of cell growth.

Genes encoding cell cycle effector proteins (E2F1,CcnD1,Cdc6,p21,p27) and DNA damage (ATM,Gadd45?²) are differentially regulated by E2Fs and NFκBs; yet the mechanisms driving concerted actions of NFκBs and E2Fs in response to mitogenic or genotoxic stimuli in normal vs cancer cells remain poorly understood.

Our proposal is targeted to define how crosstalk and balance between NFκB and E2F activities engender stable epigenetic changes that contribute to cellular programming leading to cancer development. Several experimental systems will address these questions:

  1. Normal human lung fibroblasts and tumor cells deficient in either IKKα or IKKβ or expressing activated IKKα or IKKβ mutants to investigate IKK-dependent effects on chromatin and transcriptional activities of direct E2F targets, and miRNA alterations that impact on NFκB-E2F crosstalk.
  2. The endogenous effects of IKK?± and IKK?² for urethane- and K-Ras-induced lung cancer will be investigated with novel lung-specific bitransgenic mice (IKKf/f:Spc-CreERT2), that induce IKK deletion in response to 4-hydroxytamoxifen (4OHT) to study their role during lung cancer progression and their impact on NFκB/E2F targets.
  3. Alterations in NFκB and E2F activities will be investigated in a panel of pre- and cancerous human lung lesions and correlated with physiological changes linked with cancer development. We will define the mechanistic interplay between NFκBs and E2Fs impacts on lung cancer development.

Project info

Acronym:
CancerTFs
Coordinating Institution:
University of Ioannina
Scientific Coordinator:
Kolettas Evangelos
Research Team 2 Leader:
Thanos Dimitrios
Research Team 3 Leader:
Gorgoulis Vassilis
Research Team 4 Leader:
Sandaltzopoulos Rafael

Stats

I.D.:
141
Mis:
379435
Duration (months):
42
Budget:
600 000.00
Diavgeia:
ΑΔΑ: Β4Λ59-ΒΡΤ

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