DISCOVERY REDEFINES FINAL MOMENT OF CELL DIVISION 

Breakthrough findings may have important implications for research on cancer, aging and stem cell development 

OCTOBER 6, 2005

WORCESTER,
Mass. - Basic biology textbooks will have to be re-written based on the breakthrough discoveries reported today by the University of Massachusetts Medical School, where researchers have found that the  final moment when human cells divide  is not a simple matter of pulling apart and the resulting cells are not identical twins.

A team led by  Stephen J. Doxsey , PhD, UMMS professor of molecular medicine, biochemistry & molecular pharmacology, and cell biology, discovered that when human cells divide, one of the new daughter cells actually causes the separation by blasting away from the other, and the other daughter cell is then left with a protein-packed ring structure that marks it as the older cell and could be an important element of aging and cell death. These and other findings of the Doxsey team are published in the October 7, 2005 edition of the journal  Cell.  

"We're very excited about these results.  We believe this opens up a new area of research on aging and, potentially, on how stem cells divide and maintain their ability to keep dividing without differentiating," Dr. Doxsey said. "There also may well be important implications for cancer research because a hallmark of tumor cells is their ability to divide indefinitely. We'll want to explore if these ring structures affect cell division in tumors."

The published findings are based on multiple experiments on the process of abscission, which is the final moment when two cells divide. Doxsey's team worked with human cell lines, but their findings appear to be widely applicable to all animal cells. Heretofore, it was believed that after a mother cell had gone through mitosis, with its chromosomes replicated and separated, new cell membranes would form around the two daughter cells and contract,  pulling the daughters apart in a sort of cellular tug of war that left two identical cells. Just before final separation, the prospective daughter cells are joined by an increasingly thin stretch of material (the intracellular bridge), which ultimately snaps apart.  At the center of that bridge, there is a dense midpoint- previously called the "Flemming body" or the "residual body" which was believed to have little, if any functional role in cell division.  "This is a part of basic biology that was essentially overlooked until very recently," Doxsey said. "Think about the language involved, 'the residual body;' who would want to study something so unimportant and boring?"

But through a serendipitous twist, Doxsey and his team found themselves studying that residual body intensely. And what they discovered is that the structure, which they have named the midbody ring, is a vital and active element of cell division. It is round, like a doughnut, composed of multiple active proteins, and tethered to filaments that extend back into each nascent daughter cell.  Doxsey's team also discovered that just before the cells divide, only one of the daughters sends a rush of vesicles down the intracellular bridge. These vesicles, which are small sacks of fluid not unlike water balloons, build up on only one side of the midbody ring, then fuse together or burst to break the bonds and achieve final separation. Doxsey's team also found that when the vesicles fuse and abscission occurs, the midbody ring is left with the cell that did not send in the vesicles.

"To have this kind of polarity-all these vesicles rushing in from just one side during cell division-was really never expected," Doxsey said. "We believe the midbody ring becomes a marker for the older cell. In addition, these rings appear to persist on the cell surface-we've seen cells with as many as six of these midbody rings on one cell. So, there are many questions that need to be explored about the function of those rings, both before and after abscission."

Doxsey is a leader in the study of cell division. His lab is at the forefront of researching the molecular mechanisms that can cause normal cells to mutate into cancerous cells. Much of that work focuses on the centrosome, a small part of a cell that helps chromosomes line up properly during cell division. In a series of papers in major journals, Doxsey has shown that in nearly all solid tumors, including breast, prostate, lung, brain and cervical cancers, the centrosomes are defective either in number, or structure, or both. Doxsey also demonstrated that the centrosome defects are present very early in pre-cancerous lesions, including human papilloma virus (HPV) induced cervical abnormalities. In addition, the degree of centrosomal defects in certain lesions is correlated to the aggressiveness of the cancer that may eventually develop.

Doxsey's examination of the process of abscission grew out of his centrosome studies, when his team found that a prolific centrosome protein they identified called centriolin was found, by happenstance, to be present in significant quantities at the former residual body.

The University of Massachusetts Medical School, one of the fastest growing academic health centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research.  The Medical School attracts more than $174 million in research funding annually, 80 percent of which comes from federal funding sources. UMMS is the academic partner of UMass Memorial Health Care, the largest health care provider in Central Massachusetts. For more information visit  www.umassmed.edu .

Contact: Michael Cohen, 508.856.2000, Michael.Cohen@umassmed.edu