期刊
BIOCHEMICAL JOURNAL
卷 449, 期 -, 页码 275-284出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20120625
关键词
inhibitor of nuclear factor kappa B kinase (IKK); iron; nuclear factor kappa B (NF-kappa B); transferrin; transferrin receptor 1 (TfR1); tumour necrosis factor alpha (TNF alpha)
资金
- Tenovus Scotland
- Association for International Cancer Research (AICR)
- Cancer Research UK
- Biotechnology and Biological Sciences Research Council
- Cancer Research UK [12918] Funding Source: researchfish
The IKK [inhibitor of NF-kappa B (nuclear factor kappa B) kinase] complex has an essential role in the activation of the family of NF-kappa B transcription factors in response to a variety of stimuli. To identify novel IKK-interacting proteins, we performed an unbiased proteornics screen where we identified TfR1 (transferrin receptor 1). TfR1 is required for transferrin binding and internalization and ultimately for iron homoeostasis. TfR1 depletion does not lead to changes in IKK subunit protein levels; however, it does reduce the formation of the IKK complex, and inhibits TNF alpha (tumour necrosis factor alpha)-induced NF-kappa B-dependent transcription. We find that, in the absence of TfR1, NF-kappa B does not translocate to the nucleus efficiently, and there is a reduction in the binding to target gene promoters and consequentially less target gene activation. Significantly, depletion of TfR1 results in an increase in apoptosis in response to TNF alpha treatment, which is rescued by elevating the levels of RelA/NF-kappa B. Taken together, these results indicate a new function for TfR1 in the control of IKK and NF-kappa B. Our data indicate that IKK-NF-kappa B responds to changes in iron within the cell.
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