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4 INSIDE SALK

SUMMER 2016

WWW.SALK.EDU

DISCOVERIES

At noon every day, levels of genes and

proteins throughout your body are

drastically different than they are at

midnight. Disruptions to this 24-hour

cycle of physiological activity are why jet

lag or a bad night’s sleep can alter your

appetite and sleep patterns for days—and

even contribute to conditions like heart

disease and cancers.

Now, scientists led by Ronald Evans have

discovered a key player—a protein called

REV-ERB—that controls the strength of

this circadian rhythm in mammals. The

discovery, publishedMay 2016 in

Cell

, is

unusual in the field, as most circadian

genes and proteins only shift the timing

or length of the daily cycle.

The study’s first author Xuan Zhao,

Evans and colleagues analyzed levels

and molecular characteristics of REV-

ERB in the livers of mice. After the

protein’s levels peaked during the day,

two other proteins, CDK1 and FBXW7,

reduced REV-ERB to a low point by

the middle of the night. When the team

targeted these proteins to block the

degradation of REV-ERB, normal daily

fluctuations in gene expression were

suppressed, but the timing of the cycles

wasn’t affected. Altering the strength

of the gene expression oscillations

profoundly affected metabolism,

disrupting the levels of fats and sugars in

the blood. What’s more, mice that lacked

REV-ERB developed fatty liver disease,

stressing the importance of regulating

the intensity of the cycle.

POWERING UP

THE CIRCADIAN

RHYTHM

METABOLISM

Salk Professor Reuben Shaw’s lab

revealed how a cellular “fuel gauge”

responsible for managing energy

processes—a protein complex called

AMPK—has an unexpected role in

development. The work was published

March 2016 in

Genes & Development

.

Shaw, first author Nathan Young and

colleagues discovered that embryonic

stem cells without a functioning

AMPK pathway don’t execute the

development process properly, creating

more of one germ layer than another.

This lapse turns out to be due to a loss

of lysosomes, structures responsible

for degrading and reusing cellular

components. By turning on lysosomal

genes, the teamwas able to restore

normal development in the AMPK-

deficient cells.

According to Shaw, the connection

between AMPK and lysosomes reveals

more about cellular growth and

metabolism.

Currently, lysosome inhibitors are in

dozens of clinical trials for certain

cancers, even though the exact link

between lysosomes and tumors is

not understood. “We are decoding

underlying connections that might

indicate when and how cancer drugs

might be useful,” says Shaw. “This

work may help us make better, more

specific ways of targeting lysosomes

in cancer.”

A Salk team revealed a link between

cellular recycling centers called

lysosomes and the development of

different layers of cells in an organism.

This image shows a well-differentiated

structure derived from normal embryonic

stem cells, with all nuclei stained blue.

Only one layer of cells (endoderm, green)

contains high levels of lysosomes (red).

Credit: Anwesh Kamireddy/Salk Institute

SALK SCIENTISTS UNCOVER HOW

A CELL’S “FUEL GAUGE” PROMOTES

HEALTHY DEVELOPMENT