MOLECULAR ANALYSIS OF THE NEVOID BASAL CELL CARCINOMA GENE

痣样基底细胞癌基因的分子分析

• 批准号: 6160940
• 负责人: M DEAN
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6160940
• 关键词: basal cell carcinoma; clinical research; developmental genetics; gene expression; gene mutation; genetic disorder; genetic mapping; genetic markers; human genetic material tag; human subject; neoplasm /cancer genetics; nevus

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, keratocysts of the jaw, and a variety of other tumors and developmental abnormalities. The NBCCS gene is located on chromosome 9q22.3; and both familial and sporadic BCCs display loss of heterozygosity for markers in this region. We have previously shown that the NBCCS gene is the human homolog of the Drosophila patched (PTC) gene. Patched is a segment polarity gene, essential for embryonic development. Single-stranded conformation polymorphism analysis and sequencing revealed mutations of PTC in patients with the syndrome and in familial and sporadic basal cell carcinoma (BCC) tumors. PATCHED is the receptor for the HEDGEHOG protein, a morphogen. HEDGEHOG binding releases PATCHED from repression of SMOOTHENED (SMO) a 7-transmembrane protein that initiates the signal. PATCHED is part of a complex feedback pathway in which <PTC mRNA is induced to produce excess free PATCHED and turn off the signalling pathway. In support of this we found that PTC message is overexpressed in many BCCs. Thus as in the Drosophila system, an absence of functional PTC leads to constituitive SMO signalling and elevated PTC mRNA. To further explore the role of this pathway in malignancy we have mapped the human SMO gene to chromosome 7q21. We have sequenced the 3' untranslated region of both the mouse and human genes and shown that there is extensive conservation. This suggests that there are conserved regulatory sequences in the gene. The finding that the pathways critical for the development of the embryo and adult tissues are also important to growth control, suggests that these two processes are interconnected and that other members of the HEDGEHOG and PATCHED signalling pathways may also be involved in neoplasia.

痣样基底细胞癌综合征（NBCCS）是一种常染色体遗传病 以多发性基底细胞癌为特征的显性疾病 （基底细胞癌）、手掌和脚底凹陷、下颌角化囊肿和 各种其他肿瘤和发育异常。 NBCCS 基因 位于染色体 9q22.3 上；以及家族性和散发性 BCC 显示该区域标记的杂合性丢失。我们有 先前表明 NBCCS 基因是人类的同源基因 果蝇修补（PTC）基因。 patched是片段极性基因， 对胚胎发育至关重要。单链构象 多态性分析和测序揭示了 PTC 的突变 患有该综合征的患者以及家族性和散发性基底细胞 癌（BCC）肿瘤。 PATCHED 是 HEDGEHOG 的受体 蛋白质，一种形态发生素。 HEDGEHOG 结合释放 PATCHED 的抑制 SMOOTHENED (SMO) 是一种启动信号的 7 次跨膜蛋白。 PATCHED 是复杂反馈途径的一部分，其中 <PTC mRNA 诱导产生过量的游离 PATCHED 并关闭信号 途径。为了支持这一点，我们发现 PTC 消息被过度表达 在许多密件抄送中。因此，正如在果蝇系统中一样，缺乏功能性 PTC 导致组成型 SMO 信号传导和 PTC mRNA 升高。到 进一步探索我们已绘制的该通路在恶性肿瘤中的作用 人类SMO基因位于染色体7q21。我们已经对 3' 进行了测序 小鼠和人类基因的非翻译区并表明 有广泛的保护。这表明存在保守的 基因中的调控序列。研究发现这些途径至关重要 对于胚胎和成体组织的发育也很重要 生长控制，表明这两个过程是相互关联的 HEDGEHOG 和 PATCHED 信号通路的其他成员 也可能参与肿瘤形成。