The disease familial cylindromatosis results from the loss of a gene called CYLD, causing tumors known as cylindromas to develop in hair-follicle cells. Earlier studies indicated a role for CYLD in inflammation, but the mechanism behind the gene's control over tumor growth had remained uncertain.
A team led by Reinhard Fässler of the Max Planck Institute of Biochemistry in Germany and his colleagues has now found that CYLD has a second role that explains its ability to keep tumors at bay.
The enzyme chemically modifies the cancer-promoting protein Bcl-3, first identified in connection with some forms of leukemia. That modification bars the oncogenic protein's entry into the cell nucleus, the central command center and storehouse for DNA, where it would otherwise drive the uncontrolled increase in cell numbers characteristic of tumor growth.
The researchers first showed that mice lacking CYLD were highly sensitive to developing skin tumors. Mutant mice exposed to particular chemicals all developed skin tumors compared to half of normal mice experiencing the same exposures. Moreover, the CYLD-deficient mice developed 7-fold more and significantly larger tumors than their control littermates.
Further examination of tumors taken from the mutant mice suggested that the defect stemmed from an increase in cell proliferation rather than cell survival. Isolated CYLD-deficient skin cells, when treated with the tumor-inducing chemicals, began to proliferate due to an accumulation of Bcl-3 in the nucleus, they found. Treatment with a single dose of ultraviolet light--thought to be a trigger of cylindromas--sparked the same reaction in the mutant cells, they found.
"In the absence of CYLD, it is the accumula
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Source:Cell Press