MOLECULAR ANALYSIS OF THE NEVOID BASAL CELL CARCINOMA GENE

痣样基底细胞癌综合征（NBCCS）是一种常染色体 以多发性基底细胞癌为特征的显性疾病 （基底细胞癌），手掌和脚底的凹陷，颌骨的角化囊肿，以及 各种其他肿瘤和发育异常。NBCCS基因 位于染色体9q22.3;家族性和散发性BCC 显示该区域标记的杂合性缺失。我们有 先前表明，NBCCS基因是人类的同源物， 果蝇patched（PTC）基因。Patched是一个片段极性基因， 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， 家族性和散发性基底细胞癌 癌（BCC）肿瘤。PATCHED是刺猬的受体 蛋白质，形态发生素HEDGEHOG结合从抑制中释放PATCHED SMOOTHENED（SMO）是一种启动信号的7跨膜蛋白。 PATCHED是一个复杂的反馈途径的一部分，其中<PTC mRNA是 诱导产生过量的游离PATCHED并关闭信号传导 通路为了支持这一点，我们发现PTC信息是过度表达的， 在许多BCC中。因此，在果蝇系统中， PTC导致组成型SMO信号传导和升高的PTC mRNA。到 进一步探索这一通路在恶性肿瘤中的作用， 将人SMO基因定位于染色体7 q21。我们已经测序了 小鼠和人类基因的非翻译区，并表明， 有广泛的保护。这表明有保守的 基因中的调节序列。这一发现表明， 对于胚胎和成体组织的发育也很重要 到生长控制，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。

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.