Fig. 1: Photographs showing the correlation between Rap1 (left) and NF-κB (right) in respectively stained breast cancer tissue.
Reproduced from Ref. 1. © V. Tergaonkar
Repressor activator protein 1 (Rap1) is a protein with many roles. In budding yeasts, Rap1 is involved in regulating telomere turnover, transcription and chromatin remodeling. In mammalian cells, Rap1 plays a role in maintaining telomere length and protecting telomere ends. However, recent studies have shown that unlike yeast Rap1, mammalian Rap1 does not have a domain for binding DNA. For this reason, many scientists speculate that mammalian Rap1 may not play a role in transcription or chromatin remodeling.
Vinay Tergaonkar at the A*STAR Institute of Molecular and Cell Biology and co-workers have now identified the role of mammalian Rap1 in transcription. They found that although mammalian Rap1 has lost the ability to bind DNA, the protein could control transcription by regulating the activity of the transcription factor NF-κB.
NF-κB is an important regulator of transcription and a key participant in a variety of cellular processes, including cell division and cell responses to infection. Under normal conditions, inhibitory proteins called IκBs (inhibitors of κB) bind and restrict the activity of NF-κB in the cytoplasm. When cells receive appropriate signals, special enzymes called IKKs (IκB kinases) would phosphorylate and disassociate IκB proteins to activate NF-κB. Recent studies have found that IKKs could also phosphorylate and modify the p65 subunit of NF-κB, which is needed by NF-κB to function properly as a transcription factor.
The researchers carried out a ‘gain-of-function’ screen to search for novel regulators of NF-κB in the human genome and identified mammalian Rap1 as a potential candidate. They found that mammalian Rap1 could bind IKKs to form complexes, and that these complexes are essential for the phosphorylation of p65 but not of IκB. They also found that mutant mice lacking Rap1 are resistant to endotoxic shock — a sign of defective NF-κB activation — and that tumor samples from breast cancer patients have high levels of Rap1 and NF-κB.
Together, the results demonstrate that mammalian Rap1 is an adaptor of IKKs and a critical regulator of NF-κB. An interesting finding is that, unlike yeast Rap1, mammalian Rap1 does not control transcription directly. Instead, mammalian Rap1 controls transcription through the regulation of NF-κB activity.
“Independent findings by two other groups have also revealed extra roles played by Rap1 in mammals, showing that Rap1 in mammals can function away from the telomeres,” says Tergaonkar.
NF-κB signaling has important implications in aging and cancer development. Rap1, being a regulator of NF-κB signaling, may well be a novel therapeutic target for anti-aging and anti-cancer therapy.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology.
