Role of cell cycle regulatory molecules in retinoic acid- and vitamin D3-induced differentiation of acute myeloid leukaemia cells
Role of cell cycle regulatory molecules in retinoic acid- and vitamin D3-induced differentiation of acute myeloid leukaemia cells
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DOI：
10.1111/cpr.12100
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发表时间：
2014-06-01
影响因子：
8.5
通讯作者：
Zuckerman, K. S.
中科院分区：
文献类型：
--
作者：
Hu, X. T.;Zuckerman, K. S.
细胞周期调控分子在所有反式维甲酸（ATRA）和维生素D3诱导的生长抑制和分化诱导中的重要作用已在急性髓性白血病原代细胞和各种白血病细胞系中得到深入研究。细胞周期蛋白依赖性激酶（CDK）激活激酶已被证明与急性早幼粒细胞白血病细胞中的视黄酸受体（RAR）相互作用，ATRA抑制CDK激活激酶导致PML-RAR磷酸化不足，导致髓样分化。在许多情况下，ATRA和维生素D3下调CDK活性是p21和p27结合CDK升高的结果。p21的激活在转录水平上受到调节，而升高的p27由（间接）转录激活和翻译后修饰引起。INK家族的CDK抑制剂（CKIs），如p15、p16和p18，主要参与抑制细胞增殖，而CIP/KIP成员，如p21，调节生长停滞和诱导分化。ATRA和维生素D3也可下调G1期CDK的表达，尤其是CDK 2和CDK 6。仅在ATRA中观察到细胞周期蛋白E表达的抑制，但在维生素D3处理的白血病细胞中未观察到。在体外，ATRA和维生素D3不仅需要pRb的去磷酸化，而且需要总pRb的升高来抑制生长并触发它们的分化。最后，在用ATRA处理的几种白血病细胞系中观察到c-Myc的急剧减少，这可能调节CDKs和CKIs的表达。
The important role of cell cycle regulatory molecules in all trans-retinoic acid (ATRA)- and vitamin D3-induced growth inhibition and differentiation induction has been intensively studied in both acute myeloid leukaemia primary cells and a variety of leukaemia cell lines. Cyclin-dependent kinases (CDK)-activating kinase has been demonstrated to interact with retinoic acid receptor (RAR) in acute promyelocytic leukaemia cells, and inhibition of CDK-activating kinase by ATRA causes hypophosphorylation of PML-RAR, leading to myeloid differentiation. In many cases, downregulation of CDK activity by ATRA and vitamin D3 is a result of elevated p21- and p27-bound CDKs. Activation of p21 is regulated at the transcriptional level, whereas elevated p27 results from both (indirectly) transcriptional activation and post-translational modifications. CDK inhibitors (CKIs) of the INK family, such as p15, p16 and p18, are mainly involved in inhibition of cell proliferation, whereas CIP/KIP members, such as p21, regulate both growth arrest and induction of differentiation. ATRA and vitamin D3 can also downregulate expression of G1 CDKs, especially CDK2 and CDK6. Inhibition of cyclin E expression has only been observed in ATRA- but not in vitamin D3-treated leukaemic cells. In vitro, not only dephosphorylation of pRb but also elevation of total pRb is required for ATRA and vitamin D3 to suppress growth and trigger their differentiation. Finally, sharp reduction in c-Myc has been observed in several leukaemia cell lines treated with ATRA, which may regulate expression of CDKs and CKIs.