Cell Biology

M.L. Fero, M. Rivkin, M. Tasch, P. Porter, C.E. Carow, E. Firpo, K. Polyak, L.-H. Tsai, V. Broudy, R.M. Perlmutter, K. Kaushansky, J.M. Roberts, "A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27Kip1-deficient mice," Cell, 85:733-44, 1996. (Cited in more than 100 publications to date) Comments by Matthew L. Fero, division of basic sciences, Fred Hutchinson Cancer Research Center, Seattle GIGANTIC MICE: Matthew Fero of the Fred Hutchinson Cancer Research Center found that p27-deficient mice were significantly larger than normal littermates. Observing the complexity and precision of timing of cell growth, you might think a "ghost in the machine" or an invisible hand orchestrated the whole process. But researchers in cell biology have made significant advances in understanding the miracle of how cells know when to stop growing and dividing. Cyclin-dependent kinases (CDKs), together with their cyclin protein subunits, trigger the sequence of the cell-division cycle. Discovered in 1993, p27 is a member of a new, widely studied class of inhibitory proteins that bind cyclin-CDK complexes and arrest cell division. This class to which p27 belongs--the Kip/Cip inhibitors--also includes the inhibitors p21 and p57. The inhibitor p27 is unique in terms of its responsiveness to a wide variety of mitogenic and antimitogenic signals. For example, interleukin-2, an extracellular factor produced by white blood cells, causes p27 levels to drop and induces proliferation in lymphocytes. To gain further insight on p27, a research team headed by Matthew L. Fero, an investigator in the division of basic sciences at the Fred Hutchinson Cancer Research Center in Seattle, produced mice with a targeted deletion (knockout) of the p27 gene. Surprisingly, the larger mice did not have increased body fat. The increased weight was in part attributable to the proportional enlargement of internal body organs. The research team did observe, however, that the thymus, spleen, and pituitary gland enlarged disproportionately. An additional observation was that heterozygous mice, which carry only half the normal number of p27 genes, were intermediate in size. This shows that the growth abnormality is not an all-or-nothing phenomenon and that the amount of p27 is an important factor in growth. At the most basic level, this experiment helped to confirm the causal role of p27 in the regulation of cell proliferation. "However, it is important to note not just what we observed, but what we did not observe," Fero says. "We did not see animals with uncontrollable, relentless cellular proliferation. There are at least two alternative explanations for this. Cells could have redundant mechanisms that, for the most part, can compensate for abnormal loss of p27. Alternatively, one of the major functions of p27 could be to determine the overall size of an animal, for example, by determining the maximum number of times a cell can divide in maturing tissues." Although p27-nullizygous male mice sired normal-sized litters, researchers found that nullizygous females were sterile. The reason for this seems to be complex and involves impaired ability to release eggs during the estrous cycle and an impaired ability of the female uterus to adequately support the needs of a growing embryo. Because of the fertility and growth abnormalities of the animals, the research team took careful steps to assess their endocrine status. Levels of all the relevant hormones turned out normal, and the anterior portion of the pituitary, which secretes these factors, turned out not to be involved in tumor growth. The pituitary tumors arose strictly from the gland's intermediate lobe. Similar abnormalities have been observed in retinoblastoma (Rb) knockout mice. The Rb protein is a cell cycle inhibitor with many functional similarities to p27. Mice with a single mutation in the Rb gene previously have been bred by other research groups; they also developed these highly unusual pituitary tumors. Because these tumors are otherwise so incredibly rare in mice, the fact that they are induced by deletion of either p27 or Rb is strong genetic confirmation that these molecules operate in a similar or identical biochemical pathway. Fero says there are a variety of reasons why the study has attracted wide interest. "Understanding the cell cycle and the roles that various molecules [play] in its regulation is of fundamental importance to biologists and biomedical researchers," he explains. "Before the article appeared, scientists already had considerable interest in the processes of cellular growth and development. Our study adds to this knowledge and may ultimately have significant implications for the treatment of human disease." For example, an understanding of p27 and other CDK inhibitors eventually could allow scientists to harness their activity as tumor suppressors. Fero's study appeared in Cell along with another highly cited article on the function of p27 in cell development (H. Kiyokawa et al., Cell, 85:721-32, 1996).

Cell Biology

The Scientist Staff

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