Cell Biology

Edited by: Karen Young Kreeger S.F. Dowdy, P.W. Hinds, K. Louie, S.I. Reed, A. Arnold, R.A. Weinburg, "Physical interaction of the retinoblastoma protein with human D cyclins," Cell, 73:499-511, 1993. (Cited in 150 publications through February 1995) M.E. Ewen, H.K. Sluss, C.J. Sherr, H. Matsushime, J. Kato, D.M. Livingston, "Functional interactions of the retinoblastoma protein with mammalian D-type cyclins," Cell, 73:487-97, 1993. (Cited in 163 publications through February 1995) Comments by Steven F. Dowdy, Washington University School of Medicine and Howard Hughes Medical Institute; and Mark E. Ewen, Dana Farber Cancer Institute and Harvard Medical School The two articles describe the physical interactions between the retinoblastoma protein and D cyclins, a basic discovery in cell biology that has ramifications for the study of cancer. Both types of proteins are important in regulating the cell cycle, the many-step process of cellular division and replication. The retinoblastoma protein--called pRb for short--is also significant because the gene encoding pRb is found mutated in a subset of human cancers, resulting in pRb's inactivation. At the same time, the hyperactivation of cyclins and their associated catalytic enzymes, called kinases, also leads to pRb inactivation and cancerous growth. The first authors of the two papers--Steve Dowdy, an assistant professor in the division of molecular oncology at Washington University School of Medicine and an assistant investigator with the Howard Hughes Medical Institute; and Mark Ewen, an assistant professor of medicine at the Dana Farber Cancer Institute and Harvard Medical School--call pRb a "check-point" molecule in the cell cycle. Dowdy explains: "pRb's default mode is to stop cellular division. That's its role in life, unless it's specifically turned off." These papers characterize the functional interactions between pRb and the three D cyclins, together with their associated kinases. Cyclins function to activate cyclin-dependent kinases, which facilitate adding phosphates onto other molecules that play a role in cell-cycle progression. And, as the data presented in these papers show, the phosphorylation of pRb--via cyclin-dependent kinases--correlates with an inactivation of its ability to arrest cellular division. Specifically, if pRb is inactivated, a cell will proceed through the cell cycle, multiplying unchecked until the pRb is again activated. Herein lie the implications for cancer biology. Some of the so-called tumor-suppressor genes, such as the retinoblastoma gene, are "the red stop lights and the oncogenes are the green lights" in the control of the cell cycle, remarks Dowdy. "Cancerous growth occurs when the red light is broken--that is, when pRb is inactivated. And when the green light is always on, that is when oncogenes are hyperactivated." The articles, although produced independently in different laboratories, complement and corroborate each other, according to Dowdy and Ewen. "Eighty percent of the data in the two papers matches," notes Dowdy. He adds that "the crux of the two papers is that pRb binds to D cyclins via the pocket [a specific region of pRb] and that it doesn't do this with any of the other cyclins." The studies, however, homed in on different details, namely emphasizing investigations on different types of cyclins and their role in regulating cellular division. Ewen explains: "The major difference between the two papers is that in the model that I put forward, I purported that the D cyclins affect the function of pRb by mediating the phosphorylation of it; whereas Steve's model said that pRbs bind to D cyclins, thereby preventing cell cycle progression." He adds: "It's a matter of who's affecting whom." The reason for the disparity between the two results, Ewen conjectures, "is that perhaps cyclin D1 is doing something different than what cyclin D2 is doing." Results for cyclin D3, however, are similar in both papers. Dowdy calls the fact that there are different results for D1 and D2 "fruitful," in that it can lead to distinguishing differences between their roles in cell division in different cell types. Both authors speculate that the reason the papers are so highly cited is that understanding cell-cycle regulation is important in studying human malignancies, and, more specifically, because the altering of pRb's normal function by some D cyclins is associated with several types of cancer. "Because there was open communication between the two labs throughout the investigations," comments Dowdy, "it allowed for what we like to see in science--a lot of corroboration of the primary data and communication of the results prior to publication."

Cell Biology

Interested in reading more?

Become a Member of