Cenp-F, A Novel Cell-Cycle Specific Protein That Is Involved in Chromosomal Segregation During Mitosis
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The goal of mitosis is the production of two identical, genetically equivalent daughter cells from the parent cell. This process requires a set of carefully orchestrated events that ensure that the parent cell DNA is properly replicated and parsed to the nascent cells. Several genes act in tandem to direct the various processes, many in a cell-cycle dependent manner. One of the more critical events in cell division is chromosomal segregation. In this process, chromosomes that have aligned themselves at the cell equator are linked with the mitotic spindle (comprised primarily of microtubules) and, following a final proofreading phase, are pulled away from the equator toward the poles. The point of attachment is the kinetochore, a structure located at the chromosomal centromere. Several cell cycle regulated centromeric proteins localize at the kinetochore and mediate the attachment of the chromosome to the spindle. One such protein, designated CENP-F, is up-regulated in the G2 and M phases of the cell cycle. However, it associates with the kinetochore only during M phase (mitosis itself). During G2, CENP-F is associated with the nuclear matrix.
As part of their ongoing studies of the mechanisms of cell division, FCCC investigators have isolated a gene whose product is localized at the kinetochore, a discreet structure that mediates microtubule binding to the chromosome during mitosis.
Markers of cellular proliferation are useful tools in assessing the growth fraction of tumors, give important prognostic information, and are valuable in stratifying patients for various treatment protocols. However, a reliable and widely accepted growth marker for tumors has yet to be established. Studies of currently used markers such as Ki-67, KiSi, and PCNA have yielded contradictory results. Moreover, visualization of these antigens has proven to be dependent on the tissue preparation and fixative procedures used.
CENP-F gives a strong antibody response in malignant tumors and other proliferative diseases independent of the tissue preparation procedures used. Also, routine screening revealed the presence of autoantibodies to CENP-F in the majority of autoimmune patients. Knockout experiments in cultured cells have shown that cells deficient in CENP-F are unable to divide. Taken together, these data suggest that CENP-F may be a viable target for anti-mitotic drugs as well as a valuable marker for cellular proliferation. A simple drug screen could be set up using anti-CENP-F antibodies to assess the effects novel compounds have on the cell growth.
Use of CENP-F as a proliferative marker would allow the clinician to evaluate the effectiveness of antimitotic therapies with much more accuracy and higher resolution than with currently available techniques. This evaluation can be performed earlier in the course of treatment than measuring tumor bulk, allowing for fine-tuning of chemotherapy sooner rather than later in treatment. Moreover, CENP-F antibodies, applied in concert with other tumor markers will be useful for assessing pre-malignant conditions (e.g. dysplastic lesions), allowing for early intervention and treatment.
In the research laboratory, anti-CENP-F antibodies can be utilized as screening tools in the search for new, more effective chemotherapeutic agents. Further, cell cycle studies will be facilitated by allowing researchers to determine the specific phase of the cycle the cells within a given population are in and to study kinetochore function during mitosis.
J.B. Rattner, A. Rao, M.J. Friztler. D.W. Valencia, and T.J. Yen. (1993) CENP-F is a ca.400 kDa kinetochore protein that exhibits a cell-cycle dependent localization. Cell Motility and the Cytoskeleton 26:214-226.
H. Liao, R.J. Winkfein, G. Mack, J.B. Rattner, and T.J. Yen. (1995) CENP-F is a protein of the nuclear matrix that assembles onto kinetochores at late G2 and is rapidly degraded after mitosis. Journal of Cell Biology 130:507-518.
A U.S. patent application on the DNA has issued. U.S. and foreign patent applications for the CENP-F protein and methods of use are currently pending.
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