Nordic Life Science 1
anu Jaakkola was a postdoctoral fellow in the Rat
cliffe group and a first author on the lab’s groundbreaking paper. “We knew that HIF had to be marked somehow,” says Jaakola, now professor and research director at Helsinki University Hospital Cancer Center. “It was surprising that it was with prolyl hydroxylation.” At the time, this modification was known only for the structural protein collagen. And what was known came from Finland. “When we understood that this was prolyl hydroxylation,” Jaakkola says, “I contacted Kari Kivirikko.” “Kari Kivirikko in Oulu has been a world expert on collagen hydroxylases for decades,” says Ratcliffe, “He was a natural person to talk to.” The Kivirikko lab contributed advice and Myllyharju did assays confirming that collagen hydroxylases do not modify HIF. The discovery of HIF-specific prolyl hydroxylases, Ratcliffe says, was an “aha” moment. The University of Oulu continues to be strong in the field, says Kappinen. She was a PhD student with Kivirikko and explains how he launched studies on hydroxylases and their larger enzyme family of dioxygenases when he started at Oulu in the early 1970s. “When Ratcliffe and Kaelin discovered HIF prolyl hydroxylases,” she says, “we had a jump start.” Oulu scientists had activity assays and protein production systems for studying related enzymes, so they did the first indepth biochemical analyses of the HIF-modifying enzymes. 58 NORDICLIFESCIENCE.ORG