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May I have this dance? Nuclear chaperones guide transcription factors to DNA

Proteins that guide transcription factors from the nuclear membrane to the DNA cause drug-resistant skin cancers and are new targets for drug development.

Lately, I've been addicted to period dramas, some of which are more historically accurate than others, (I'm thinking "The Crown", "Victoria" and, my latest, more-guilty pleasure, "The White Princess"). My favorites have female protagonists struggling to assert themselves under the watchful eye of the various companions, guardians and advisors that shepherd them through their days.

My viewing habits are probably responsible for my train of thought during a discussion recently with dermatologist Anthony Oro, MD, PhD. Oro was describing how a protein in the nucleus chaperones a transcription factor called Gli1 from its temporary station on the nuclear membrane to the DNA, much like how the women in my favorite dramas are guided from the ballroom door to the dance floor by attentive partners, I imagined.

Despite my fanciful musings, however, this previously unknown chaperoning process may prove critical to drug developers working to combat treatment-resistant cancers. Oro and graduate student Amar Mirza published their findings recently in Cell.

As Oro described:

We've learned that Gli1 is escorted from the moment it enters the nucleus. It's first bound to the nuclear membrane before being handed off to a complex of proteins that escort it to the DNA so it can enhance the expression of genes that cause the tumor to grow. Furthermore, we found that resistant tumors essentially co-opt this chaperoning system and delivers Gli1 to the DNA faster and faster. If we block this handoff, we can dramatically reduce Gli1 activity in resistant tumors.

I've written before how Gli1 activity (one step in a cascade of cellular signaling interactions known as the hedgehog pathway) is critical to the development of a common skin cancer called basal cell carcinomas. Although these tumors are usually successfully treated, it's common for them to eventually become resistant to current drug treatments. Identification of this new interaction late in the hedgehog pathway gives researchers a potential new target for therapies.

As Oro explained:

In the past, it was not thought possible to use transcription factors as drug targets. It was believed that they enter the nucleus and just float over the DNA to turn on genes. Once it is in the nucleus there appeared to be no real intervention points to target. This is a true paradigm shift in terms of our ability to target oncogenic transcription factors in the nucleus.

The work also emphasizes the importance of the network of proteins, lipids and other molecules that comprise the nuclear membrane.

As Oro said:

This is another paradigm shift. Previously, we've focused a lot of attention on the cell cytoskeleton. But now we know that the nuclear cytoskeleton and its associated proteins also perform critical functions. They provide the tracks on which the chaperoning complex deliver the transcription factor to the DNA. They are not just there as eye candy, so to speak. Without this direction, or in the absence of the chaperone, the transcription factor is degraded or pumped out of the nucleus.

It's probably clear from my watchlist that I have nothing against a little eye candy now and again. But joking aside, it's beyond important to find new ways to fight these common skin cancers and I'm honored to have the chance to hear about each step in the process from researchers like Oro.

Photo by machaon-dance

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