MicroRNA-15a fine-tunes the level of Delta-like 1 homolog (DLK1) in proliferating 3T3-L1 preadipocytes
MicroRNA-15a fine-tunes the level of Delta-like 1 homolog (DLK1) in proliferating 3T3-L1 preadipocytes
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DOI：
10.1016/j.yexcr.2010.04.002
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发表时间：
2010-06-10
影响因子：
3.7
通讯作者：
Sheikh, Soren P.
中科院分区：
文献类型：
--
作者：
Andersen, Ditte C.;Jensen, Charlotte H.;Sheikh, Soren P.
Delta like 1 homolog（Dlk 1）以跨膜和可溶性分子形式存在，并且与细胞生长有关，在发育、组织再生和癌症中起多种作用。因此，DLK 1水平对于细胞功能至关重要，DLK 1表达异常可能是致命的：然而，人们对潜在机制知之甚少。我们在此报道了miR-15 a调节前脂肪细胞中DLK 1的水平，从而提供了DLK 1调节的机制，进一步将其与细胞周期停滞和癌症联系起来，因为miR-15 a在这些过程中被去调节。在前脂肪细胞中，miR-15 a随着细胞密度增加而增加，并在膜DLK 1（M）和可溶性DLK 1（S）达到最大水平的同一阶段达到峰值。值得注意的是，miR-15 a在mRNA水平上抑制所有Dlk 1变体的量，但也抑制DLK 1（M）蛋白的水平，同时它增加DLK 1（S）的量，支持DLK 1的直接抑制和对从膜上切割DUO的蛋白酶的平行作用。与以前的研究一致，我们发现miR-15 a抑制细胞数量，但另外，我们报告miR-15 a也增加细胞大小。相反，抗miR-15 a处理降低细胞大小，同时增加细胞数量，通过添加纯化的DLK 1（S）完全挽救的情况因此，我们的数据暗示miR-15 a通过微调Dlk 1等来调节细胞大小和增殖，并进一步强调miR-15 a和DLK 1水平在生长信号传导网络中发挥重要作用。(c)2010年爱思唯尔公司All rights reserved.
Delta like 1 homolog (Dlk1) exists in both transmembrane and soluble molecular forms, and is implicated in cellular growth and plays multiple roles in development, tissue regeneration, and cancer. Thus, DLK1 levels are critical for cell function, and abnormal DLK1 expression can be lethal: however, little is known about the underlying mechanisms. We here report that miR-15a modulates DLK1 levels in preadipocytes thus providing a mechanism for DLK1 regulation that further links it to cell cycle arrest and cancer since miR-15a is deregulated in these processes.In preadipocytes, miR-15a increases with cell density, and peaks at the same stage where membrane DLK1(M) and soluble DLK1(S) are found at maximum levels. Remarkably, miR-15a represses the amount of all Dlk1 variants at the mRNA level but also the level of DLK1(M) protein while it increases the amount of DLK1(S) supporting a direct repression of DLK1 and a parallel effect on the protease that cleaves off the DUO from the membrane. In agreement with previous studies, we found that miR-15a represses cell numbers, but additionally, we report that miR-15a also increases cell size. Conversely, anti-miR-15a treatment decreases cell size while increasing cell numbers, scenarios that were completely rescued by addition of purified DLK1(S).Our data thus imply that miR-15a regulates cell size and proliferation by fine-tuning Dlk1 among others, and further emphasize miR-15a and DLK1 levels to play important roles in growth signaling networks. (c) 2010 Elsevier Inc. All rights reserved.