How Cells Adjust to Low Oxygen (and Why It’s Important)

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Imagine a football team with two independent squads. One plays when it’s sunny, dry and the grass is perfect. The other comes in when conditions are more difficult — when rain or sleet have made the field a muddy mess.

Oxygen deficiency activates ‘Hyde,’ including (1) a unique mRNA cap-binding complex, eIF4FH, (2) eIF5B to facilitate initiator methionine-tRNAiMet delivery, (3) hypoxia-sensitive ribosomal proteins, and (4) networks of translatome remodeling RNA-binding proteins. The hypoxia-inducible protein HIF-2a serves as the oxygen-sensing activator of this system, which produces the translatome of hypoxia-adaptive proteins via mRNA translation efficiency reprogramming, whereas the basal translation machinery (‘Jekyll’) is deactivated via mechanisms including eIF4E1 and eIF2 inhibition.

In a series of studies published over the past few years, most recently a December 9 article in Trends in Biochemical Sciences, researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have shown that cells adopt this two-squad approach when responding to low oxygen levels (hypoxia) — a common component in many cancers.

Under normal circumstances, cells produce a specific set of proteins that translate messenger RNA (mRNA) signals into more proteins. However, when cells become hypoxic, they produce a different set of proteins to manage this process, one better suited for low-oxygen conditions. These revelations have upended how researchers view cellular responses to hypoxia.

“Everybody thought that when cells make proteins, they use a one-size-fits-all machinery,” said J.J. David Ho, Ph.D., an associate scientist at Sylvester who has been leading efforts to tackle this problem since 2014. “We used to think there was just one type of machinery, and it was either turned on or turned off, but now we understand there’s a lot of plasticity to it. Different components get mixed and matched to help cells produce the proteins they need to survive under different conditions.”

Transcription vs. translation

Scientists used to think our genomic machinery adopted a relatively simple, three-part process: DNA gets transcribed into mRNA, which gets translated into proteins that do most of the work in cells. If more work needs to be done, the machinery transcribes more mRNA. If the cell must respond to environmental stresses, like hypoxia, it transcribes different genes.

While this model is accurate, it’s also incomplete. Working closely with principal investigators Stephen Lee, Ph.D., professor of biochemistry and molecular biology and Jonathan Schatz, M.D., associate professor of medicine, and colleagues, Dr. Ho has shown this translational system is far more complex than previously thought.

“We discovered an unknown variant in the protein synthesis machinery,” Dr. Ho said. “This particular ‘persona’ of the translational apparatus allows cells, especially cancer cells, to produce a different repertoire of proteins to survive and respond to oxygen deprivation.”

In other words, the transcription process at the DNA level doesn’t contribute as much as we thought. Rather, cells modify how the RNA is handled to custom-design protein production to better manage hypoxia.

Prior to this work, many scientists thought hypoxia shuts down protein synthesis, ignoring that protein synthesis continues to be very active in hypoxic cells. But to gain this better understanding, the Sylvester researchers had to develop a whole new way to assess protein synthesis in real time. Their proteomic platform, called MATRIX, generates unbiased translational system blueprints, providing a much more detailed picture of how and which proteins are being created and when.

Hypoxia and cancer

Tumors grow so fast they often outrun their supply lines — the blood flow that delivers oxygen and nutrients — and yet they survive and even thrive. This new understanding of how cells respond to hypoxia could generate better approaches to cancer therapies, as researchers dive deeper into this alternative translational apparatus and develop compounds that can inhibit it.

Beyond hypoxia, cells also activate specific translation machineries in response to other stresses. In a recent study co-led by Nathan C. Balukoff, an M.D./Ph.D. candidate and NCI F30 fellow at the Miller School, and Dr. Ho, researchers in the Lee laboratory identified a key translation factor (an enzyme that helps control gene expression), eIF5A, which is activated when the environment outside cells become acidic. This process promotes cellular dormancy, during which cancer cells go to sleep to escape chemotherapy and other treatments.

These findings could have a major impact on the therapeutic landscape. Merck and other companies have drugs in clinical trials that could modulate tumor responses to hypoxia, making it easier to kill them.

“This is a radical reconfiguration of our vision of what cells do under hypoxic and other stressful conditions,” Dr. Ho said. “We are diving deep into this dark side of the hypoxic translation machinery, and we believe it will produce a number of therapeutic opportunities for cancer and perhaps other conditions.”