Dissecting the novel partners of nuclear c-Raf and its role in all-trans retinoic acid (ATRA)-induced myeloblastic leukemia cells differentiation.
Dissecting the novel partners of nuclear c-Raf and its role in all-trans retinoic acid (ATRA)-induced myeloblastic leukemia cells differentiation.
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DOI：
10.1016/j.yexcr.2020.111989
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发表时间：
2020-09-01
影响因子：
3.7
通讯作者：
Yen, Andrew
中科院分区：
文献类型：
--
作者：
Rashid, Asif;Wang, Rui;Zhang, Liang;Yue, Jianbo;Yang, Mengsu;Yen, Andrew
全反式维甲酸（ATRA）是一种抗癌分化治疗剂，对急性早幼粒细胞白血病（APL）有效，但一般对急性髓细胞白血病（AML）无效。使用HL-60人非APL AML模型，其中ATRA引起c-Raf的核富集，从而驱动分化和G1/G 0细胞周期停滞，我们现在观察到细胞核中的c-Raf与细胞周期和细胞分化的几个主要调节因子表现出新的相互作用。一种是细胞周期蛋白依赖性激酶2（Cdk 2）。ATRA处理导致c-Raf与Cdk 2解离。这与Cdk 2与视黄酸受体α（RARα）的结合增强有关。与这种促进分化的新Raf/CDK 2/RARα轴一致，每个细胞的CD 38表达（由视黄酸反应元件（RARE）转录调节）增强。RB肿瘤抑制因子是G1期细胞周期进展或停滞的基本调节因子，也被细胞核中的c-Raf靶向。RB，特别是与c-Raf复合的S608磷酸化形式（pS 608 RB）。ATRA处理诱导S608 RB-低磷酸化与G1/G 0细胞周期阻滞和c-Raf从RB释放。我们还发现，核c-Raf与SMARD 1相互作用，SMARD 1是SWI/SNF染色质重塑复合物的先驱成分。ATRA治疗减少了这种蛋白结合到c-Raf的量。这些数据表明，ATRA治疗HL-60人细胞重定向c-Raf从其历史上促增殖功能在细胞质中的细胞核中的促分化功能。
All-trans retinoic acid (ATRA) is an anti-cancer differentiation therapy agent effective for acute promyelocytic leukemia (APL) but not acute myeloid leukemia (AML) in general. Using the HL-60 human non-APL AML model where ATRA causes nuclear enrichment of c-Raf that drives differentiation and G1/G0 cell cycle arrest, we now observe that c-Raf in the nucleus showed novel interactions with several prominent regulators of the cell cycle and cell differentiation. One is cyclin-dependent kinase 2 (Cdk2). ATRA treatment caused c-Raf to dissociate from Cdk2. This was associated with enhanced binding of Cdk2 with retinoic acid receptor α (RARα). Consistent with this novel Raf/CDK2/RARα axis contributing to differentiation, CD38 expression per cell, which is transcriptionally regulated by a retinoic acid response element (RARE), is enhanced. The RB tumor suppressor, a fundamental regulator of G1 cell cycle progression or arrest, was also targeted by c-Raf in the nucleus. RB and specifically the S608 phosphorylated form (pS608RB) complexed with c-Raf. ATRA treatment induced S608RB-hypophosphorylation associated with G1/G0 cell cycle arrest and release of c-Raf from RB. We also found that nuclear c-Raf interacted with SMARCD1, a pioneering component of the SWI/SNF chromatin remodeling complex. ATRA treatment diminished the amount of this protein bound to c-Raf. The data suggest that ATRA treatment to HL-60 human cells re-directed c-Raf from its historically pro-proliferation functions in the cytoplasm to pro-differentiation functions in the nucleus.
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影响因子：
--
作者：
Bunaciu RP;MacDonald RJ;Gao F;Johnson LM;Varner JD;Wang X;Nataraj S;Guzman ML;Yen A
通讯作者：
Yen A
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
2.9
作者：
Hong, HY;Varvayanis, S;Yen, A
通讯作者：
Yen, A
影响因子：
4
作者：
Lamkin, TJ;Chin, V;Yen, A
通讯作者：
Yen, A
DOI：
10.1016/j.bbamcr.2013.01.015
发表时间：
2013-05-01
影响因子：
5.1
作者：
Leicht, Deborah T.;Balan, Vitaly;Tzivion, Guri
通讯作者：
Tzivion, Guri