BAP1 has a survival role in cutaneous melanoma.
BAP1 has a survival role in cutaneous melanoma.
复制标题
DOI：
10.1038/jid.2014.528
复制
发表时间：
2015-04
影响因子：
6.5
通讯作者：
Tsao, Hensin
中科院分区：
文献类型：
--
作者：
Kumar, Raj;Taylor, Michael;Miao, Benchun;Ji, Zhenyu;Njauw, Jenny C-N;Jonsson, Goran;Frederick, Dennie T.;Tsao, Hensin
虽然在眼黑色素瘤标本和BAP1皮肤/眼黑色素瘤(CM/OM)易感综合征中BAP1失活的模式提示了肿瘤抑制功能，但该基因在皮肤黑色素瘤发病机制中的具体作用尚不完全清楚。因此，我们开始研究BAP1在皮肤黑色素瘤中的特征，并发现这种蛋白具有意想不到的促生存作用。组织和细胞系分析表明，与色素痣和正常皮肤相比，BAP1在原发性黑色素瘤中的表达保持不变，而不是丢失。黑色素瘤细胞中BAP1的基因缺失降低了黑色素瘤细胞的增殖和集落形成能力，诱导了细胞凋亡，抑制了黑色素瘤的生长。在分子水平上，抑制BAP1导致Survivin的蛋白水平随之下降，Survivin是抗凋亡蛋白的成员，也是黑色素瘤生存的已知中介。黑色素瘤细胞中Survivin的恢复部分挽救了BAP1缺失对生长的抑制作用。与黑色素瘤细胞相比，BAP1在永生化但未转化的黑素细胞中稳定过表达确实抑制了增殖并减少了Survivin。综上所述，这些研究表明，BAP1可能在黑色素瘤细胞中起到维持生长的作用，但它对泛素化的影响支持了一种复杂的生理机制，这是上下文和细胞依赖的。
Although the pattern of BAP1 inactivation in ocular melanoma specimens and in the BAP1 cutaneous/ocular melanoma (CM/OM) predisposition syndrome suggests a tumor suppressor function, the specific role of this gene in the pathogenesis of cutaneous melanoma is not fully understood. We thus set out to characterize BAP1 in cutaneous melanoma and discovered an unexpected pro-survival effect of this protein. Tissue and cell lines analysis showed that BAP1 expression was maintained, rather than lost, in primary melanomas compared to nevi and normal skin. Genetic depletion of BAP1 in melanoma cells reduced proliferation and colony forming capability, induced apoptosis and inhibited melanoma tumor growth in vivo. On the molecular level, suppression of BAP1 led to a concomitant drop in the protein levels of survivin a member of anti-apoptotic proteins and a known mediator of melanoma survival. Restoration of survivin in melanoma cells partially rescued the growth-retarding effects of BAP1 loss. In contrast to melanoma cells, stable overexpression of BAP1 into immortalized but non-transformed melanocytes did suppress proliferation and reduce survivin. Taken together, these studies demonstrate that BAP1 may play a growth-sustaining role in melanoma cells, but that its impact on ubiquitination underpins a complex physiology which is context and cell dependent.
登录
查看更多内容
DOI：
10.1126/science.1194472
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Harbour JW;Onken MD;Roberson ED;Duan S;Cao L;Worley LA;Council ML;Matatall KA;Helms C;Bowcock AM
通讯作者：
Bowcock AM
影响因子：
30.8
作者：
Wiesner, Thomas;Obenauf, Anna C.;Murali, Rajmohan;Fried, Isabella;Griewank, Klaus G.;Ulz, Peter;Windpassinger, Christian;Wackernagel, Werner;Loy, Shea;Wolf, Ingrid;Viale, Agnes;Lash, Alex E.;Pirun, Mono;Socci, Nicholas D.;Ruetten, Arno;Palmedo, Gabriele;Abramson, David;Offit, Kenneth;Ott, Arthur;Becker, Juergen C.;Cerroni, Lorenzo;Kutzner, Heinz;Bastian, Boris C.;Speicher, Michael R.
通讯作者：
Speicher, Michael R.
影响因子：
21.3
作者：
Kittler, Ralf;Pelletier, Laurence;Buchholz, Frank
通讯作者：
Buchholz, Frank
影响因子：
11.5
作者：
Harbst, Katja;Staaf, Johan;Jonsson, Goran
通讯作者：
Jonsson, Goran
影响因子：
30.8
作者：
Pena-LlopiS, Samuel;Vega-Rubin-de-Celis, Silvia;Liao, Arnold;Leng, Nan;Pavia-Jimenez, Andrea;Wang, Shanshan;Yamasaki, Toshinari;Zhrebker, Leah;Sivanand, Sharanya;Spence, Patrick;Kinch, Lisa;Hambuch, Tina;Jain, Suneer;Lotan, Yair;Margulis, Vitaly;Sagalowsky, Arthur I.;Summerour, Pia Banerji;Kabbani, Wareef;Wong, S. W. Wendy;Grishin, Nick;Laurent, Marc;Xie, Xian-Jin;Haudenschild, Christian D.;Ross, Mark T.;Bentley, David R.;Kapur, Payal;Brugarolas, James
通讯作者：
Brugarolas, James