Genetics

H. Kiyokawa, R.D. Kineman, K.O. Manova-Todorova, V.C. Soares, E.S. Hoffman, M. Ono, D. Khanam, A.C. Hayday, L.A. Frohman, and A. Koff. "Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27Kip1," Cell, 85:721-32, 1996. (Cited in more than 155 papers since publication) Comments by Andrew Koff, associate member of the molecular biology program, Memorial Sloan-Kettering Cancer Center, New York Cyclin-dependent kinase (CDK) inhibitors act as a traffic cop of cell division. However, the precise signals these proteins issue to direct cells have eluded researchers. Andrew Koff and colleagues proposed three potential ways these proteins might stop and start cellular proliferation: as a "restriction point" regulator that controls entry into both differentiation and division as a "checkpoint" system that stops division in response to genetic damage as a "holding" function that keeps cells in a nonproliferative state "The question that then comes up is, 'How do you identify a cell type which is displaying any one of those functions for any one of the different CDK inhibitors?'" Koff notes. A definitive answer remained elusive, since seven known CDK inhibitors had been identified and tagged with similar roles. Each of those may overlap with another, and each may participate in some or all of the three transitions to control cell cycling. Koff's group and two others explored this problem by making a mouse without CDK inhibitor p27. All three groups observed the same results--the p27 knockout mice grew larger than their control counterparts (M.L. Fero et al., Cell, 85:733-44, 1996; See Hot Papers commentary by M.L. Fero, The Scientist, 12[7]:11, March 30, 1998), (K. Nakayama et al., Cell, 85:707-20, 1996; See Hot Papers commentary by N. Nakayama, 12[21]:11, Oct. 26, 1998). All three groups also reported that cell proliferation, not excess fat, caused the p27 knockouts' girth. "In 1996, we speculated that the increase in animal size was due to an increase in cell numbers because of increased proliferation, prior to withdrawal of cells from the cell cycle. This was consistent with our failure to identify changes in either growth hormone, which mediates animal growth," Koff recollects. All three papers received heavy citation attention because p27 plays key roles in many cellular processes, Koff suspects. "Commitment into the cell cycle affects many different processes. It affects endocrine processes, tumorogenesis processes, the way that cells talk to each other, the way that development occurs." But none of the papers definitively addressed which of the three means p27 employed to control differentiation and proliferation. All three groups hypothesized that the p27 deficiency resulted in loss of restriction-point control. However, studying the mouse phenotype alone didn't rule out unsuspected endocrine effects as factors enhancing proliferation. The three groups also had hypothesized how p27 deficiency contributed to infertility in female mice, but had no hard data. Consequently, studies on cells isolated from the animal were required to confirm the putative restriction-point role as an integrator of signal transduction pathways that control differentiation. Exploring this question were Koff's group, in collaboration with Moses Chao, of the Cornell University Graduate School of Medical Science (P. Casaccia-Bonnefil et al., Genes and Development, 11:2335-46, 1997), and another group led by Martin Raff, of the Imperial Cancer Research Foundation, in collaboration with James M. Roberts, the senior author of the Fero paper (B. Durand et al., Current Biology, 8:431-40, April 9, 1998). Both groups isolated and cultured precursor cells in p27-deficient mouse brains. "They would differentiate, but they would do so much slower, which was entirely consistent with the proliferation phenotypes observed within the mouse model," Koff remarks. "It provided a sort of proof of a restriction-point role." However, the two groups reached different conclusions about the cause of infertility in female p27-deficient mice. Koff's group, in collaboration with Jeffrey Pollard at Albert Einstein College of Medicine, concluded that the deficiency prevents production of the hormones progesterone and estrodial (W. Tong et al., Cell Growth and Differentiation, 9:787-94, September 1998). Roberts' group blamed defective uterine response. Koff suspects that genetic differences between the two groups' transgenic mice may explain the discrepancy. Although both follow-up papers more firmly establish the role of p27 as a restriction protein-controlling commitment into cell cycling, the other two roles have been neither proved nor excluded--meaning fertile but challenging grounds for future research. Koff also anticipates that more researchers will attack the problem of how other signaling molecules control p27. "When we can start to understand how the protein is regulated, we can start linking into the antimitogenic signals that are controlling differentiation or development," he says.

Genetics

The Scientist Staff

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