Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF.
Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF.
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DOI：
10.1371/journal.pone.0002734
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发表时间：
2008-07-16
期刊：
影响因子：
3.7
通讯作者：
Marais R
中科院分区：
文献类型：
--
作者：
Wellbrock C;Rana S;Paterson H;Pickersgill H;Brummelkamp T;Marais R
小眼症相关转录因子（MITF）是黑素细胞中细胞类型特异性功能的重要调节因子。MITF对于色素细胞的存活是必不可少的，但是尽管高水平的MITF驱动黑素细胞分化，但需要较低水平的MITF来允许黑色素瘤细胞的增殖和存活。MITF被ERK磷酸化，这刺激其活化，但也通过泛素-蛋白体途径靶向其降解，将MITF降解与其活化偶联。我们先前已经表明，由于ERK在BRAF突变的黑色素瘤细胞中过度活化，因此MITF蛋白质组成性下调。在这里，我们描述了另一个有趣的方面，MITF调节致癌BRAF在黑色素瘤细胞。我们发现致癌BRAF通过ERK和转录因子BRN 2（N-Oct 3）上调MITF转录。相反，我们表明，在黑素细胞中，这种途径不存在，因为BRN 2不表达，表明MITF调节是一种新获得的致癌BRAF功能，而不是由野生型蛋白质执行。重要的是，在黑色素瘤细胞中，MITF是致癌BRAF下游所必需的，因为它调节关键细胞周期调节蛋白如CDK 2和CDK 4的表达。野生型BRAF在黑素细胞中不调节该途径。因此，我们表明，致癌BRAF发挥精致的控制MITF在两个层面上。它通过刺激蛋白质的降解来下调蛋白质，但随后通过增加BRN 2的转录来抵消这种作用。我们的数据表明，致癌BRAF在调节MITF表达，以确保其蛋白质水平与黑色素瘤细胞的增殖和存活相容中起着关键作用。我们认为，它的能力，适当的调节这一关键因素部分解释了为什么BRAF是这样一个强大的癌基因在黑色素瘤。
The Microphthalmia-associated transcription factor (MITF) is an important regulator of cell-type specific functions in melanocytic cells. MITF is essential for the survival of pigmented cells, but whereas high levels of MITF drive melanocyte differentiation, lower levels are required to permit proliferation and survival of melanoma cells. MITF is phosphorylated by ERK, and this stimulates its activation, but also targets it for degradation through the ubiquitin-proteosome pathway, coupling MITF degradation to its activation. We have previously shown that because ERK is hyper-activated in melanoma cells in which BRAF is mutated, the MITF protein is constitutively down-regulated. Here we describe another intriguing aspect of MITF regulation by oncogenic BRAF in melanoma cells. We show oncogenic BRAF up-regulates MITF transcription through ERK and the transcription factor BRN2 (N-Oct3). In contrast, we show that in melanocytes this pathway does not exist because BRN2 is not expressed, demonstrating that MITF regulation is a newly acquired function of oncogenic BRAF that is not performed by the wild-type protein. Critically, in melanoma cells MITF is required downstream of oncogenic BRAF because it regulates expression of key cell cycle regulatory proteins such as CDK2 and CDK4. Wild-type BRAF does not regulate this pathway in melanocytes. Thus, we show that oncogenic BRAF exerts exquisite control over MITF on two levels. It downregulates the protein by stimulating its degradation, but then counteracts this by increasing transcription through BRN2. Our data suggest that oncogenic BRAF plays a critical role in regulating MITF expression to ensure that its protein levels are compatible with proliferation and survival of melanoma cells. We propose that its ability to appropriate the regulation of this critical factor explains in part why BRAF is such a potent oncogene in melanoma.
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影响因子：
5.3
作者：
Goodall, J;Wellbrock, C;Goding, CR
通讯作者：
Goding, CR
MITF的表达升高抵消B-RAF刺激的黑色素细胞和黑色素瘤细胞增殖。
影响因子：
7.8
作者：
Wellbrock, C;Marais, R
通讯作者：
Marais, R
DOI：
10.1083/jcb.200410115
发表时间：
2005-01-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Loercher AE;Tank EM;Delston RB;Harbour JW
通讯作者：
Harbour JW
影响因子：
64.8
作者：
Carreira, S;Goodall, J;Goding, CR
通讯作者：
Goding, CR
影响因子：
11.2
作者：
Hoeflich, MP;Gray, DC;Seshagiri, S
通讯作者：
Seshagiri, S