每個人身上都有大小不等的黑痣,，大多數(shù)長年不變,，但有些也會發(fā)展成惡性黑色素瘤（一種皮膚癌）。法國研究人員的一項最新研究揭示了惡性黑色素瘤的發(fā)病機制,，這項成果發(fā)表在最新一期美國《基因與發(fā)育》（Gene and Development）雜志上。
黑痣中的黑色素細胞往往在經(jīng)過初期的分裂增殖后進入衰老期,，停止繼續(xù)分裂,。然而經(jīng)過數(shù)年的“休眠”后,，某些黑痣中已經(jīng)衰老的黑色素細胞會重新開始分裂增殖,，從而形成癌細胞,。
法國國家科研中心的研究人員對黑色素細胞的分裂機制進行了長期研究,。他們發(fā)現(xiàn),，導致黑色素細胞“不死”的始作俑者是一種被稱為“β－catenin”的蛋白質(zhì),，它抑制了一種負責控制細胞衰亡的“p16Ink4a”基因的正常表達,，從而導致已經(jīng)衰老的黑色素細胞又重新開始分裂增殖。
研究人員說,，醫(yī)學界早已發(fā)現(xiàn)“β－catenin”蛋白質(zhì)在皮膚癌細胞分裂中發(fā)揮了某種作用,，但此前一直沒能揭開其導致細胞“不死”的秘密,。
法國國家科研中心11月18日發(fā)表公報說，這項研究大大推動了科學界對惡性黑色素瘤發(fā)病機制的認識,，研究人員正在此基礎上加緊研發(fā)新型治療藥物和對該病的新療法,。（新華網(wǎng)）
原始出處:
GENES & DEVELOPMENT 21:2923-2935, 2007
β-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development
Véronique Delmas1, Friedrich Beermann2,3, Silvia Martinozzi1, Suzanne Carreira4, Julien Ackermann2, Mayuko Kumasaka1, Laurence Denat1, Jane Goodall4, Flavie Luciani1, Amaya Viros5, Nese Demirkan1,6, Boris C. Bastian5, Colin R. Goding4, and Lionel Larue1,7
1 Developmental Genetics of Melanocytes, UMR 146, Centre National de la Recherche Scientifique (CNRS)-Institut Curie, 91405 Orsay Cedex, France; 2 The Swiss Institute for Experimental Cancer Research (ISREC), Swiss Institute for Experimental Cancer Research, National Center of Competence in Research Molecular Oncology, 1066 Epalinges, Switzerland; 3 Ecole Polytechnique Fédérale de Lausanne (EPFL) School of Sciences, CH-1066 Epalinges, Switzerland; 4 Signalling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 OTL, United Kingdom; 5 Department of Dermatology and Department of Pathology, University of California at San Francisco Comprehensive Cancer Center, San Francisco, California 94143, USA; 6 Pamukkale Üniversitesi, Tp Fakültesi, Patoloji Anabilim Dal, Knkl-Denizli 20003, Turkey
Tumor progression is a multistep process in which proproliferation mutations must be accompanied by suppression of senescence. In melanoma, proproliferative signals are provided by activating mutations in NRAS and BRAF, whereas senescence is bypassed by inactivation of the p16Ink4a gene. Melanomas also frequently exhibit constitutive activation of the Wnt/-catenin pathway that is presumed to induce proliferation, as it does in carcinomas. We show here that, contrary to expectations, stabilized -catenin reduces the number of melanoblasts in vivo and immortalizes primary skin melanocytes by silencing the p16Ink4a promoter. Significantly, in a novel mouse model for melanoma, stabilized -catenin bypasses the requirement for p16Ink4a mutations and, together with an activated N-Ras oncogene, leads to melanoma with high penetrance and short latency. The results reveal that synergy between the Wnt and mitogen-activated protein (MAP) kinase pathways may represent an important mechanism underpinning the genesis of melanoma, a highly aggressive and increasingly common disease.
[Keywords: Mitf; Wnt; senescence; development; tumor suppressor; oncogene]]
Received July 23, 2007; revised version accepted September 27, 2007.
