Protein That Induces Tumor Cell Apoptosis Could be Used for Cancer Treatment

Protein That Induces Tumor Cell Apoptosis Could be Used for Cancer Treatment

A protein – CITED2 – that causes cancer cells to kill themselves is showing considerable potential for use in new cancer treatments.

All cells require oxygen to function; however, cells can cope with low oxygen levels by going into ‘survival mode.’ During survival mode, a set of genes are activated by transcription factors called hypoxia-inducible factors (HIFs). HIFs are important in orchestrating responses to hypoxia.

One such HIF – called HIF-1 – has two subunits. HIF-1α and HIF-1β. HIF-1β is constantly expressed, although the alpha form is oxygen sensitive. Under normal conditions, hydroxyl groups are added to HIF-1α by prolyl hydroxylases which are recognized by von Hippel–Lindau (VHL) protein, which marks HIF-1α for destruction. When oxygen levels are low, the prolyl hydroxylases do not work and HIF-1α and HIF-1β dimerize and induce certain genes that help cells survive hypoxia.

During survival mode, HIF-1α binds to the TAZ1 part of a CREB-binding protein. However, cells are able to turn off the hypoxia response via a protein called CITED2. When oxygen levels return to normal, CITED2 binds to TAZ1 stopping the hypoxia response.

While the hypoxia response can help cells survive, it can also trigger tumors to grow faster. A strong hypoxia response can be triggered deep inside tumors which causes them to grow much faster. Some potential cancer treatments have been developed that attempt to prevent HIF-1α from binding with TAZ1 in an attempt to block the hypoxia response, although those drugs have not proved to be particularly effective.

However, a team of researchers at the Scripps Research Institute have discovered that it is possible to prevent HIF-1α from binding with TAZ1 with CITED2. Both HIF-1α and CITED2 bind to TAZ1, and while each has an equal affinity, when both are in competition with each other, CITED2 always wins and binds to TAZ1.

According to Scripps Research Institute professor Peter Wright, Ph.D., “You only need a small amount of CITED2 to switch off the hypoxic response, and no amount of HIF1α can switch it back on.”

Therefore, rather than attempting to stop HIF-1α from binding with TAZ1, it should be possible to synthesize a drug that mimics natural protein competition. A drug that mimics CITED2 and blocks the TAZ1 binding site will turn off the hypoxia response.

The paper – Hypersensitive Termination of the Hypoxic Response by a Disordered Protein Switch – has recently been published online in the journal Nature.

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