Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools.
Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools.
复制标题
作者：
黑色素瘤进展与侵袭增加相关，并且通常与小眼症相关转录因子（MITF）水平降低相关。因此，MITF的下调诱导黑色素瘤细胞的侵袭，然而对潜在的机制知之甚少。在这里，我们报告的第一次，MITF的耗竭导致细胞内GTP水平的升高和活性（GTP结合）RAC 1，RHO-A和RHO-C的量增加。同时，MITF缺失的细胞显示出更大数量的侵袭伪足和增加的侵袭。我们进一步证明，鸟苷一磷酸还原酶（GMPR）的基因是一个直接的MITF的目标，和GMPR的部分抑制占主要为上述表型在MITF-耗尽细胞。反过来，GMPR的反式激活是MITF依赖性抑制黑色素瘤细胞侵袭、致瘤性和肺定植所必需的。此外，GMPR的丧失伴随着维罗非尼抗性BRAFV 600 E-黑素瘤细胞中MITF的下调，并且是这些细胞中侵袭增加的基础。我们的数据揭示了连接MITF依赖的抑制入侵抑制鸟苷酸代谢的新机制。
Melanoma progression is associated with increased invasion and, often, decreased levels of microphthalmia-associated transcription factor (MITF). Accordingly, downregulation of MITF induces invasion in melanoma cells, however little is known about the underlying mechanisms. Here, we report for the first time that depletion of MITF results in elevation of intracellular GTP levels and increased amounts of active (GTP-bound) RAC1, RHO-A and RHO-C. Concomitantly, MITF-depleted cells display larger number of invadopodia and increased invasion. We further demonstrate that the gene for guanosine monophosphate reductase (GMPR) is a direct MITF target, and that the partial repression of GMPR accounts mostly for the above phenotypes in MITF-depleted cells. Reciprocally, transactivation of GMPR is required for MITF-dependent suppression of melanoma cell invasion, tumorigenicity, and lung colonization. Moreover, loss of GMPR accompanies downregulation of MITF in vemurafenib-resistant BRAFV600E-melanoma cells and underlies the increased invasion in these cells. Our data uncover novel mechanisms linking MITF-dependent inhibition of invasion to suppression of guanylate metabolism.
登录
查看更多内容
影响因子：
30.8
作者：
Krauthammer, Michael;Kong, Yong;Ha, Byung Hak;Evans, Perry;Bacchiocchi, Antonella;McCusker, James P.;Cheng, Elaine;Davis, Matthew J.;Goh, Gerald;Choi, Murim;Ariyan, Stephan;Narayan, Deepak;Dutton-Regester, Ken;Capatana, Ana;Holman, Edna C.;Bosenberg, Marcus;Sznol, Mario;Kluger, Harriet M.;Brash, Douglas E.;Stern, David F.;Materin, Miguel A.;Lo, Roger S.;Mane, Shrikant;Ma, Shuangge;Kidd, Kenneth K.;Hayward, Nicholas K.;Lifton, Richard P.;Schlessinger, Joseph;Boggon, Titus J.;Halaban, Ruth
通讯作者：
Halaban, Ruth
影响因子：
4.3
作者：
Hoek, Keith S.;Schlegel, Natalie C.;Steingrimsson, Eirikur
通讯作者：
Steingrimsson, Eirikur
影响因子：
64.5
作者：
Hotary, KB;Allen, ED;Weiss, SJ
通讯作者：
Weiss, SJ
影响因子：
11.4
作者：
Fink EE;Mannava S;Bagati A;Bianchi-Smiraglia A;Nair JR;Moparthy K;Lipchick BC;Drokov M;Utley A;Ross J;Mendeleeva LP;Savchenko VG;Lee KP;Nikiforov MA
通讯作者：
Nikiforov MA
影响因子：
12.4
作者：
Bianchi-Smiraglia, A.;Wawrzyniak, J. A.;Nikiforov, M. A.
通讯作者：
Nikiforov, M. A.