Role of MAFF in dampening Nrf2 signal

A study (R1) was conducted on patients with AD and PD. It found significant downregulation of genes that are directly controlled by Nrf2, which was upregulated.

MAFF was found to be upregulated in all tissues and negatively correlated with NRF2-dependent genes, suggesting its role in the dysfunction of the NRF2 regulatory network.

Comparing the differentially expressed genes between AD and PD, we identified 54 common genes shared by more than six tissues. Among them, 31 downregulated genes contained the antioxidant response element (ARE) consensus sequence bound by NRF2.

NRF2 is a transcription factor, which protects cells against oxidative stress through coordinated upregulation of ARE-driven genes. To our surprise, although NRF2 was upregulated, its target genes were all downregulated.

Further exploration found that MAFF was upregulated in all tissues and significantly negatively correlated with the 31 NRF2-dependent genes in diseased conditions.

Previous studies have demonstrated over-expressed small MAFs can form homodimers and act as transcriptional repressors. Therefore, MAFF might play an important role in dysfunction of NRF2 regulatory network in PD and AD. (R1)

MafF is upregulated in Hepatitis B virus infection

MafF physically binds to the HBV core promoter and competitively inhibits HNF-4α binding to an overlapping sequence in the HBV enhancer II sequence (EnhII), as seen by chromatin immunoprecipitation (ChIP) analysis.

MafF expression was induced by interleukin-1β (IL-1β) or tumor necrosis factor alpha (TNF-α) treatment in both HepG2 and PXB cells, in an NF-κB-dependent manner.

Consistently, MafF expression levels were significantly enhanced and positively correlated with the levels of these cytokines in patients with chronic HBV infection, especially in the immune clearance phase. (R2)

MafF expression is induced by IL1b and TNFa.

MafF is upregulated by hypoxia

In this study, we identified hypoxia-induced v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a HIF-1 target gene, which is regulated by hypoxia. Our data indicate that while MAFF does not affect primary tumor growth, it promotes disease progression by increasing the invasive and metastatic behavior of tumor cells.

Here, we demonstrate that MAFF, which is induced by HIF-1 under hypoxia, binds with BACH1 and promotes tumor invasion and metastasis by transcriptionally activating IL11 and promoting STAT3 pathways. (R4)