A mechanism known as "oncogene-induced senescence" can block most cancer types and is commonly seen when incipient skin cancers turn into slow-growing moles instead of malignant tumors. Tumors that achieve malignancy often do so by defeating or circumventing this barrier. However, scientists have been unable to find out precisely how the mechanism works – until now.
A TSRI team has uncovered how the interaction of three enzymes triggers a common type of oncogene-induced senescence. The ability to force this mechanism could create a new approach to treating cancer.
"We have known about some of the molecular signals that mediate this senescence response, but we've needed to understand the signaling pathway in much more detail," said team member Peiqing Sun, an associate professor in TSRI’s Department of Cell and Molecular Biology.
Research Associate Hui Zheng and Associate Professor Peiqing Sun
Oncogenes are growth-related genes that are pushed to keep dividing beyond normal limits by DNA damage, inherited mutations, or some other cause. Oncogenes in the ras gene family are the ones that have been most frequently linked to human cancers – and most commonly studied as triggers of the senescence mechanism. A decade ago, Dr. Sun and his colleagues found that the enzyme p38 is present at the top of the response cascade that induces this mechanism, and in 2007 they discovered that p38 works by activating another enzyme known as PRAK. For the new study, Dr. Sun and first author research associate Hui Zheng, along with other members of the laboratory, sought more details of PRAK's role in this cascade.
Dr. Zheng began the investigation by searching PRAK's binding partners. With a series of protein-interaction assays, he isolated an enzyme that binds tightly to PRAK, called Tip60. Further tests showed that senescence fails to occur when Tip60 is absent, indicating that Tip60 does indeed lie within the senescence-inducing signaling cascade. Initially Dr. Zheng and Dr. Sun suspected that PRAK activates Tip60.
Instead, the reverse turned out to be true: Tip60 acts on PRAK. Tip60 is a type of enzyme called an acetyltransferase, which modifies other proteins by adding acetyl groups. "Our tests showed that Tip60 binds to PRAK and acetylates it at a certain location, which helps activate PRAK," said Dr. Zheng. Thus, activating PRAK requires two signals: first by p38 and then by Tip60.
What controls Tip60's own activation in this cascade? None other than the master switch, p38. "As a first step, p38 phosphorylates both Tip60 and PRAK," said Dr. Sun. Activated Tip60 then activates PRAK. Previously Dr. Sun and his laboratory had shown that PRAK, when activated, goes on to activate the key tumor-suppressor protein p53, which exerts more direct control over a cell's growth machinery.
Dr. Sun and his team have been looking for ways to force the activation of the senescence response in cancer cells, as a potential cancer-drug strategy. "Finding these details of the early part of the signaling cascade helps us better understand what we need to target," he said.