INHIBITION OF GRANULOCYTE DIFFERENTIATION BY G(1) CYCLINS D2 AND D3 BUT NOT D1
INHIBITION OF GRANULOCYTE DIFFERENTIATION BY G(1) CYCLINS D2 AND D3 BUT NOT D1
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DOI：
10.1073/pnas.90.24.11513
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发表时间：
1993-12-15
影响因子：
11.1
通讯作者：
SHERR, CJ
中科院分区：
文献类型：
--
作者：
KATO, JY;SHERR, CJ
生长因子诱导的信号控制着三种d型细胞周期蛋白的表达，这些细胞周期蛋白反过来又作为细胞周期蛋白依赖激酶（cdks）的调节亚基，控制G1后期的细胞周期转变。32D髓样细胞，作为白细胞介素3 （IL-3）的非承诺前体自我更新，与cdk4和cdk2复合物表达周期蛋白D2和D3（但不表达D1）。当转移到粒细胞集落刺激因子（G-CSF）时，32D细胞停止分裂并最终分化为成熟的中性粒细胞。细胞在G-CSF中生长停止，细胞周期蛋白D和cdk4的表达停止，但cdk2水平维持不变。经工程改造表达d型细胞周期蛋白的32D细胞表现出G1期缩短，S期代偿延长，但细胞生长仍依赖于IL-3；过表达周期蛋白D2和D3（但不表达D1）的细胞在G-CSF中不能分化并死亡。细胞周期蛋白D2突变体不能有效结合或功能上与视网膜母细胞瘤蛋白（pRb）或其相关蛋白（p107）相互作用，不能阻断分化。相反，将催化失活的cdk4突变体引入过表达cyclin D2的细胞中，恢复了它们的G-CSF反应。cdk2的持续存在及其倾向于与细胞周期蛋白D2和D3而不是D1相互作用，可能解释了分化阻断的特异性。
Growth factor-induced signals govern the expression of three D-type cyclins, which, in turn, function as regulatory subunits of cyclin-dependent kinases (cdks) to control cell cycle transitions during the late G1 interval. 32D myeloid cells, which self-renew as uncommitted precursors in interleukin 3 (IL-3), express cyclins D2 and D3 (but not D1) in complexes with cdk4 and cdk2. When transferred to granulocyte colony-stimulating factor (G-CSF), 32D cells stop dividing and terminally differentiate to mature neutrophils. Cyclin D and cdk4 expression ceased as cells underwent growth arrest in G-CSF, but cdk2 levels were sustained. 32D cells engineered to ectopically express D-type cyclins exhibited contracted G1 intervals with a compensatory lengthening of S phase but remained IL-3 dependent for cell growth; those overexpressing cyclins D2 and D3 (but not D1) were unable to differentiate and died in G-CSF. Cyclin D2 mutants, which cannot efficiently bind to, or functionally interact with, the retinoblastoma protein (pRb) or its relatives (p107) did not block differentiation. Conversely, the introduction of a catalytically inactive cdk4 mutant into cells overexpressing cyclin D2 restored their G-CSF response. The persistence of cdk2 and its predilection to functionally interact with cyclins D2 and D3 rather than D1 might explain the specificity of the differentiation blockade.