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首页> 外文期刊>Cell cycle >Cyclin D1 overexpression increases the susceptibility of human U266 myeloma cells to CDK inhibitors through a process involving p130-, p107- and E2F-dependent S phase entry.
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Cyclin D1 overexpression increases the susceptibility of human U266 myeloma cells to CDK inhibitors through a process involving p130-, p107- and E2F-dependent S phase entry.

机译：细胞周期蛋白D1过表达通过涉及p130-，p107-和E2F依赖的S期进入的过程，增加了人类U266骨髓瘤细胞对CDK抑制剂的敏感性。

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摘要

Dysregulation of cyclin D1 expression is one of the most common genetic aberrations found in hematopoietic malignancies, including multiple myeloma. To address the effects of cyclin D1 overexpression might have on the response of malignant hematopoietic cells to CDK inhibitors, the impact of ectopic cyclin D1 overexpression on the response of human multiple myeloma U266 cells to various cyclin-dependent kinase (CDK) inhibitors was examined. Cyclin D1 overexpression markedly increased the apoptotic response of cells to the CDK inhibitors flavopiridol, roscovitine, and R-roscovitine. Ectopic expression of cyclin D1 resulted in p21(CIP1) accumulation, an effect that was diminished by CDK inhibitor exposure. In pRb-null U266 cells, enforced overexpression of cyclin D1 diminished CDK inhibitor-mediated dephosphorylation of the pocket proteins p130 and p107, reduced binding of E2F1 and E2F4 to p130 and p107, and attenuated inhibition of E2F activity. Notably, CDK inhibitors failed to reduce the S phase fraction in cyclin D1/U266 cells in contrast to effects in their wild-type counterparts. Finally, cyclin D1/U266 cells exhibited diminished basal NF-kappaB activity compared to controls, which was essentially completely abrogated by CDK inhibitor exposure. Together, these findings suggest that dysregulation of cyclin D1 sensitizes human myeloma cells to the actions of CDK inhibitors through mechanisms involving interference with p21(CIP1) expression, dephosphorylation of pocket proteins and inactivation of E2Fs culminating in S phase entry, as well as inactivation of NF-kappaB, leading to apoptosis rather than growth arrest.
机译：细胞周期蛋白D1表达的失调是造血系统恶性肿瘤（包括多发性骨髓瘤）中最常见的遗传异常之一。为了解决细胞周期蛋白D1过表达可能对恶性造血细胞对CDK抑制剂的反应的影响，研究了异位细胞周期蛋白D1过表达对人多发性骨髓瘤U266细胞对各种细胞周期蛋白依赖性激酶（CDK）抑制剂的反应的影响。细胞周期蛋白D1的过表达显着增加了细胞对CDK抑制剂flavopiridol，roscovitine和R-roscovitine的凋亡反应。细胞周期蛋白D1的异位表达导致p21（CIP1）积累，但CDK抑制剂的暴露却减弱了这种作用。在无pRb的U266细胞中，细胞周期蛋白D1的过度表达减少了CDK抑制剂介导的口袋蛋白p130和p107的去磷酸化，降低了E2F1和E2F4与p130和p107的结合，并减弱了对E2F活性的抑制。值得注意的是，与野生型对应物相比，CDK抑制剂未能降低细胞周期蛋白D1 / U266细胞的S期分数。最后，与对照相比，细胞周期蛋白D1 / U266细胞的基础NF-kappaB活性降低，而CDK抑制剂的暴露则基本消除了该活性。在一起，这些发现表明，细胞周期蛋白D1失调使人类骨髓瘤细胞对CDK抑制剂的作用敏感，其机制涉及p21（CIP1）表达的干扰，口袋蛋白的去磷酸化和E2F的失活，最终导致S期进入，以及C21失活。 NF-κB，导致凋亡而不是生长停滞。

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