Genetics

K. Nakayama, N. Ishida, M. Shirane, A. Inomata, T. Inoue, N. Shishido, I Hori, D.Y. Loh, K. Nakayama, "Mice lacking p27 display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors," Cell, 85:707-20, 1996. (Cited in more than 155 papers since publication) Comments by Kei-ichi Nakayama, a professor of molecular and cellular biology at Kyushu University, Fukuoka, Japan Cells proliferate. Cells differentiate. Cells also occasionally stop and take a break from all of that activity. How they get from point A to point B, and how they decide when to take a breather (referred to in technical circles as cell-cycle arrest), is a subject of intense research. "There has been remarkable progress regarding p27 status and cancer."--Kei-ichi Nakayama Many proteins play roles in the process. In particular, a series of cyclin-dependent kinase complexes (CDKs) promote progression from rest phase (G) to the DNA synthesis (S) phase to cell division. These complexes phosphorylate an oncosuppressor called retinoblastoma protein (pRb), which prevents pRb from performing its normal role of suppressing transcription factors that drive proliferation. The well-known tumor suppressor p53 is one of a series of related proteins that act at the top of the chain, preventing CDK from phosphorylating pRb and thus keeping the cell cycle in check. This paper examined the resultant physical effects of mice that lack one of these inhibitors: p27. "Our hypothesis was that cell-cycle arrest is a prerequisite for differentiation, and that CDK inhibitors may play a critical role in causing cell-cycle arrest. To test the hypothesis, the obvious approach was to create CDK inhibitor knockout mice," says Kei-ichi Nakayama, a professor of molecular and cellular biology at Kyushu University, Fukuoka, Japan. The less obvious decision was which of the inhibitors in the class to knock out first. Previous research eliminated some choices. P21-knockout mice had been reported, but they showed no developmental abnormalities. P15 and p16 are expressed only at low levels in embryos, and so probably don't play a role in development, says Nakayama. On the other hand, "p27 is abundant in resting cells, while it is down-regulated as cell cycle progresses into the DNA synthesis phase. This is almost always true in many cells and systems, [with] only a few exceptions," explains Nakayama. They created the mice, and the results were eye-opening. The knockout mice had a number of abnormally large organs, including thymus, testes, and ovaries. They were also larger than their mates and had a greater tendency to develop pituitary tumors. What does it all mean? "P27 seems to be central to the regulation of cell growth," explains Nakayama. But it also plays a clear role in cancer. "There has been remarkable progress regarding p27 status and cancer," Nakayama adds. In breast, colorectal, gastric, and lung cancers, low levels of p27 in cancer cells suggest a poor prognosis. But p27 mutations aren't the problem. Rather, the protease that disposes of it is overzealous, leaving reduced levels in the cells. Although the mouse model suggests that missing p27 could be a cause of pituitary tumors, Nakayama notes that no such mutations have yet been found in human pituitary tumors. The paper probably has been highly cited because it confirmed suspicions of p27's importance. The biochemical data had shown that the protein is expressed at higher levels when cells are at rest, but, "in general, biochemical data are not counted as truth without the support of genetic evidence. Overgrowth of p27-knockout mice met people's expectations," concludes Nakayama.

Genetics

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