Dividing with IL-7
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《实验药学杂志》
PKC is required to stabilize p27kip1 in T cells deprived of IL-7.
The cytokine interleukin (IL)-7 is well known to promote T cell survival and homeostatic proliferation of T cells, with the signals required for the latter being less well understood. A study by Li et al. (page 573) now shows that IL-7 induces T cell proliferation by triggering the degradation of the cell cycle inhibitor p27kip1.
The surprising aspect of this study was not that a growth cytokine induces cell division by disposing of p27kip1—this occurs in many cell types—but that T cells have a unique way of getting rid of this protein. In most cell types, growth signals trigger the phosphorylation of p27kip1. Once phosphorylated, p27kip1 becomes bound by a Skp2 (S phase kinase-associated protein 2)-containing ubiquitin ligase complex that marks the inhibitor for proteasomal degradation.
Li and colleagues now show that p27kip1 levels were increased in T cells starved of IL-7, triggering cell cycle arrest. Although the level of Skp2 protein in these cells declined in the absence of IL-7, this decrease did not account for build-up p27kip1. Instead, the stabilization of p27kip1 required PKC (protein kinase C ), a protein not previously implicated in cell cycle control. The PKC-dependent stabilization of p27kip1 probably requires an intermediate protein, as p27kip1 has no apparent phosphorylation site for PKC. The authors are now in search of that intermediate.
Why do T cells destroy p27kip1 in their own way? One hint may lie in the requirement of IL-7 for the recombination of the T cell receptor (TCR) locus during T cell development in the thymus. Developing T cells might have devised a way to avoid activating Skp2 in response to IL-7, as a recent study showed that Skp2 also induces the degradation of Rag2, the enzyme that catalyzes TCR recombination.
The cytokine interleukin (IL)-7 is well known to promote T cell survival and homeostatic proliferation of T cells, with the signals required for the latter being less well understood. A study by Li et al. (page 573) now shows that IL-7 induces T cell proliferation by triggering the degradation of the cell cycle inhibitor p27kip1.
The surprising aspect of this study was not that a growth cytokine induces cell division by disposing of p27kip1—this occurs in many cell types—but that T cells have a unique way of getting rid of this protein. In most cell types, growth signals trigger the phosphorylation of p27kip1. Once phosphorylated, p27kip1 becomes bound by a Skp2 (S phase kinase-associated protein 2)-containing ubiquitin ligase complex that marks the inhibitor for proteasomal degradation.
Li and colleagues now show that p27kip1 levels were increased in T cells starved of IL-7, triggering cell cycle arrest. Although the level of Skp2 protein in these cells declined in the absence of IL-7, this decrease did not account for build-up p27kip1. Instead, the stabilization of p27kip1 required PKC (protein kinase C ), a protein not previously implicated in cell cycle control. The PKC-dependent stabilization of p27kip1 probably requires an intermediate protein, as p27kip1 has no apparent phosphorylation site for PKC. The authors are now in search of that intermediate.
Why do T cells destroy p27kip1 in their own way? One hint may lie in the requirement of IL-7 for the recombination of the T cell receptor (TCR) locus during T cell development in the thymus. Developing T cells might have devised a way to avoid activating Skp2 in response to IL-7, as a recent study showed that Skp2 also induces the degradation of Rag2, the enzyme that catalyzes TCR recombination.