FIG. 11.

Transcriptional regulation of ferritin H. (A) The mouse and human ferritin genes have a similar 5′-region that regulates transcription in response to external stimuli. TNF-α activates the mouse ferritin H gene through 4.8 kb upstream from the start codon, in which NF-κB is involved in this activation mechanism. Human ferritin H gene is also activated by TNF-α, but the responsible region has not been identified, although NF-κB participation was observed. Chemical and oxidative stress (such as H₂O₂, t-BHQ, hemin) activate human and mouse ferritin H gene through an antioxidant-responsive element (ARE). The ARE activation is achieved by Nrf2 and AP-1 family transcription factors synergized with p300/CBP histone acetyl transferases. Among the AP-1 family transcription factors, ATF1 serves as a repressor of ferritin H gene. Hemin and cAMP were also shown to induce ferritin genes through the proximal region, termed A- or B-box, by NF-Y transcription factors, which recruit coactivator p300/CBP proteins. Adenovirus E1A oncogene represses ferritin H transcription by inhibiting p300/CBP function. (B) Both human and mouse ferritin H genes have bidirectional ARE sequences (AP1-like and AP1/NFE2). Ferritin L has a single ARE (AP1/NFE2). The core ferritin ARE sequences are completely conserved.