Bad brakes in cell cycle linked to cancers.
In many tumor types, cells lack functional copies of p16, a protein that puts the brakes on cell division, says Tsutomu Nobori, a molecular biologist at the University of California, San Diego. In these cells, the two copies of the gene that directs production of p16 have either mutated or disappeared, he and his colleagues report in the April 21 NATURE.
They examined 46 cell lines, or groups of tumor cells, for abnormalities in the region of chromosome 9 where the p16 gene lies. About 61 percent of melanoma cell lines, 87 percent of glioma cell lines, 64 percent of leukemia cell lines, and 36 percent of non-small-cell lung cancer cell lines lacked p16 genes, Nobori reports.
The p16 gene contains three regions that direct p16 production, adds Alexander Kamb, a molecular biologist at Myriad Genetics in Salt Lake City. Independently, Kamb's group studied 12 types of cancers and detected no copies of the p16 gene in 133 of the 290 cell lines tested--a frequency of missing genes similar to that of Nobori's group. In Kamb's report in the April 15 SCIENCE, he has named this gene Multiple Tumor Suppressor 1.
The Utah researchers then analyzed melanoma cell lines for alterations as well as deletions in the p16 gene. With both included, the gene's involvement in cancer increased to 75 percent from 58 percent. They expect this trend to hold for other types of cancers, Kamb says.
"The depth of involvement of this gene [in many cancers] and the frequency with which it pops up tells us that we're really getting at the heart of the [cancer] breast," comments David Beach of the Howard Hughes Medical Institute at Cold Spring Harbor (N.Y.) Laboratory. "[These results] demonstrate clearly that there is a basic defect right at the heart of the cell cycle machinery."
The cell cycle consists of four stages: In the [G.sub.1] phase, the cell grows; in S, it makes copies of its chromosomes in [G.sub.2], it prepares to divide; and in M, the nucleus and then the cell divides (see diagram). For a cell to move from one stage to the next, different cyclin proteins must link and activate enzymes called cyclin-dependent kinases (CDK). However, proteins such as p16 and p21 can stop this progression.
Beach and his colleagues discovered the genes for p16 and p21 last December. It seems that normally, p53 activates the p21 gene whenever a cell's DNA is damaged. The resulting p21 protein freezes the cell cycle until the damage is repaired. It can stop the cell at any point because it inhibits all of the cyclin-CDK complexes that nudge the cell through these various stages of division.
But p16 targets a particular cyclin, one that works at a critical decision-making point in the cycle. At this point, a cell "decides" whether to proliferate, sit tight, or continue to grow but not divide. The researchers hope eventually to be able to influence this decision in tumor cells by adding back the MTS1 gene or administering a drug that mimics p16's braking activity. "It shows finally that all the work we've done for the last 15 years has some clinical relevance," Beach says.
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|Title Annotation:||copies of gene that helps produce protein p16, which stops cell division, are mutated or absent in many types of tumors|
|Article Type:||Brief Article|
|Date:||Apr 23, 1994|
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