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There is a time for caution and a time for committing. For the cell cycle, a halt before mitosis is an appropriate response to ionizing radiation or inhibition of DNA replication. But once mitosis is underway the cell is better off just carrying on regardless of DNA-damaging insults. Dmitry Bulavin, Albert Fornace (National Cancer Institute , Bethesda, MD), and colleagues now report on a double phosphorylation switch that keeps irradiated mitotic cells from bouncing unexpectedly out of mitosis.
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2 e! W6 \; Y" o9 f( wThe switch is in one of the Cdc25 phosphatases〞proteins that remove an inhibitory phosphate from Cdc2, thus allowing entry into mitosis. Cdc25C is itself phosphorylated during interphase. First, a constitutive kinase and then an irradiation-induced kinase hit Ser 216 on Cdc25, thus keeping the phosphatase inactive. The NCI team now show that this Ser 216 phosphorylation is replaced in mitotic cells by phosphorylation of Cdc25C on Ser 214, and that the new Ser 214 phosphorylation blocks reestablishment of the earlier Ser 216 phosphorylation. Thus, Cdc25C is locked on in mitotic cells, and does not respond to irradiation./ l( t5 g$ z6 a+ U+ ^# u
: h# g6 E3 B3 A/ U2 rThe mitosis-reinforcing function of the Ser 214 is clear from a Ser 214 to Ala mutant, which delays entry into mitosis in mammalian cells and reinstates a DNA damage replication checkpoint that is normally absent in early embryonic frog extracts. The Ser 214 residue is probably phosphorylated by Cdc2 itself, but it is unclear how the inactive Cdc25C and Cdc2 might jumpstart each other〞other Cdc25 isoforms or polo kinase are possibilities. Meanwhile, the authors suspect that pairs of mutually exclusive phosphorylation sites will turn up in other regulatory proteins, especially those that, like Cdc25C, bind to 14–3-3 proteins.5 y% R& ]( J3 c6 e
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Bulavin, D.V., et al. 2003. Nat. Cell Biol. 5:545–551.
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' f$ I; e6 ?+ C, t. ?" s! Q' p0 BBulavin, D.V., et al. 2003. Cell Cycle. 2:263–266.(Ser 214 phosphorylation (red) keeps Cdc2) |
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发表于 2009-3-6 00:54
发表于 2015-6-14 09:27
