The transcriptional repressor of p16/Ink4a, Id1, is up-regulated in early melanomas.
The transcriptional repressor of p16/Ink4a, Id1, is up-regulated in early melanomas.
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发表时间：
2001-08
期刊：
影响因子：
11.2
通讯作者：
D. Polsky;A. Z. Young;K. Busam;R. Alani
中科院分区：
文献类型：
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作者：
D. Polsky;A. Z. Young;K. Busam;R. Alani
螺旋-环-螺旋转录因子 Id1 协调哺乳动物细胞内的细胞生长和分化途径，并参与调节 G(1)-S 期细胞周期转变。最近，Id1 已被证明可以抑制 Ets 和 E 蛋白介导的 p16/Ink4a 反式激活。由于 p16/Ink4a 蛋白已被证明在家族性和散发性黑色素瘤亚群中失活，因此我们试图确定 p16/Ink4a 表达的 Id1 调节是否可能参与这种人类肿瘤的发展。在这里，我们评估了从常见黑素细胞痣到转移性黑色素瘤的不同恶性进展阶段的 21 个黑素细胞病变，并检查这些病变的 Id1 和 p16/Ink4a 表达。我们证明 Id1 表达与原位黑色素瘤中 p16/Ink4a 表达缺失相关；然而，更晚期的黑色素瘤除了血管周围区域外不表达 Id1，尽管这些病变中 p16/Ink4a 表达总体下降。对显微解剖病变进行 p16/Ink4a 序列评估，发现不表达 Id1 的侵袭性黑色素瘤具有持续失活的 p16/ink4a 突变。这些数据表明 Id1 在调节早期黑色素瘤中 p16/Ink4a 表达中的作用，并证明后来的基因变化可能导致该肿瘤晚期 p16 表达的不可逆转的丧失。
The helix-loop-helix transcription factor Id1 coordinates cell growth and differentiation pathways within mammalian cells and has been implicated in regulating G(1)-S phase cell cycle transitions. Recently Id1 has been shown to repress Ets- and E-protein-mediated transactivation of p16/Ink4a. Because the p16/Ink4a protein has been demonstrated to be inactivated in subsets of familial and sporadic melanomas, we sought to determine whether Id1 regulation of p16/Ink4a expression might be involved in the development of this human tumor. Here we evaluate 21 melanocytic lesions at various stages of malignant progression from common melanocytic nevi to metastatic melanomas and examine these lesions for Id1 and p16/Ink4a expression. We demonstrate that Id1 expression correlates with loss of p16/Ink4a expression in melanoma in situ; however, more advanced stages of melanoma do not express Id1 except within perivascular regions, despite overall decreased p16/Ink4a expression in these lesions. Microdissected lesions were evaluated for p16/Ink4a sequence, and invasive melanomas that did not express Id1 were found to have sustained inactivating p16/ink4a mutations. These data suggest a role for Id1 in regulating p16/Ink4a expression in early melanomas and demonstrate that later genetic changes may provide for irreversible loss of p16 expression in advanced stages of this tumor.