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Lowe/Elsevier" k- {# T. e0 i0 n. h8 f5 J
/ i3 J; z7 v* MTumors can proliferate by escaping failsafe programs such as apoptosis and senescence, according to Clemens Schmitt, Scott Lowe (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY), and colleagues. Although the disabling of apoptosis was well established as an escape mechanism during tumor development, the incapacitation of the senescence pathway is now shown to be an important predictor of response to drug therapy.3 [: d0 \$ `4 L' x
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Lowe and colleagues first examined which functions of p53 are needed to suppress tumor development in mice. They found that a complete block of apoptosis (using a dominant apoptosis inhibitor) removed all selective pressure of pretumorigenic cells to lose p53, and could reproduce the aggressive growth phenotype normally seen after p53 loss. This suggests that other p53-related phenotypes, such as aneuploidy and defective cell cycle checkpoints, are unimportant byproducts of p53 loss. "To those who believe that the initial event is to provide genomic instability," says Schmitt, "this is a surprise."2 U. \5 K" X0 A+ w6 U2 y
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Once drug therapy begins, however, one of those previously irrelevant byproducts becomes important. Drugs can apparently put some cells out of commission by sending them into a stress-induced senescence, but this pathway is dependent on the normal function of both p53 and the p16INK4a tumor suppressor. Cells that lack the wild-type versions of one or both of these proteins can avoid senescence, and such cells are associated with a poor response to drug treatment.Restoration of the senescence pathway may be one way to improve existing chemotherapies. But the effectiveness of this treatment will depend on just how irreversible the senescent state really is〞a problem that Schmitt and Lowe intend to investigate next.
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References:9 O* v. l; L3 H- B
* c5 m" {+ J6 w* m$ J8 RSchmitt, C.A., et al. 2002. Cancer Cell. 1:289–298. Schmitt, C.A., et al. 2002. Cell. 109:335–346.(Cells suppress tumors using both apoptos) |
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发表于 2009-3-6 00:19
发表于 2015-6-1 07:53
