Cdk fashions

The Scientist Staff
Jun 30, 2006

"In science," says Michele Pagano, "unfortunately, there are fashions." In the 1990s, it was fashionable to call mammalian cyclin-dependent kinases (Cdks) essential. Then a series of knockout experiments called those findings into question, leading to a new fashion: that Cdks are not important. Now Philipp Kaldis, of the National Cancer Institute, and colleagues have set the record straight, says Pagano, a Faculty of 1000 member from the New York University Cancer Institute.

Cdks and cyclins form complexes whose intrinsic kinase activities enable cell-cycle transitions at G1/S and G2/M. Kaldis' team generated Cdk2/Cdk4 double knockout mice, which die at embryonic day 15 (E15).1 "Cdk2 by itself is not essential, Cdk4 by itself is not essential, but together they are very important as they control the expression of Cdk1," Pagano says. "This is a significant clarification for the field."

The paper further identifies the retinoblastoma protein (Rb) as a key target for both Cdks in vivo. "Despite dozens of papers on cultured cells, it was never really true that when you lose a Cdk in vivo, the phosphorylation of Rb was significantly affected," Pagano says. "In the Cdk2/Cdk4 knockout just published, we see for the first time a severe impairment of Rb phosphorylation." That, in turn, downregulates E2F targets such as Cdk1, though why this occurs at E15 remains unclear.

1. C. Berthet et al., "Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation," Dev Cell, 10:563-73, May 2006.