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Fig. 2 | Cellular & Molecular Biology Letters

Fig. 2

From: TRIM8: a double-edged sword in glioblastoma with the power to heal or hurt

Fig. 2

Schematic representation of the oncogenic activity of TRIM8 as a positive regulator of TNF- and IL1B-triggered NFKB and transcriptional induction of genes involved in autophagosome formation. The TNF and IL1 family of cytokines are the best-characterized triggers of autophagy through activation of NFKB. TRIM8 is important for TNF- and IL1B-induced NFKB activation by interacting with MAP3K7/TAK1, which is required for NFKB activation, and mediating K63-linked polyubiquitination. The MAP3K7/TAK1-TABs complex phosphorylates IKBKB/IKKβ and CHUK/IKKa, which further activate the NFKB transcription factor by phosphorylating and degrading NFKBIA/IκBα (NFKB inhibitor alpha). Once degraded, the NFKB dimer (RELA/p65-NFKB1/p50 subunits) translocates to the nucleus, where it binds to the DNA consensus sequence of genes involved in autophagy induction, such as BECN1, ATG5, MAP1LC3/LC3, and SQSTM1/p62. These genes are involved in lysosome biogenesis and autophagy flux, which in cancer cells promote tumorigenesis even under stress conditions and protect cells from cell death due to DNA damage. TRIM8 also counteracts the negative effect of PIAS3 on NFKB through polyubiquitination and degradation of PIAS3. Upon genotoxic stress, TRIM8 stabilizes XIAP, leading to activation of NFKB via the activating SMAD and MAPK/JNK signaling pathways. As a result, apoptosis in cancer cells is suppressed and cell growth is positively controlled. Cytokines such as IFNG and IL1 increase TRIM8 expression through activation of the JAK- STAT pathway and due to the existence of a continuous positive feedback loop between STAT3 and TRIM8

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