Contribution of N-ras loss to metastasis of thyroid C-cell tumors

描述(申请人提供)：视网膜母细胞瘤蛋白(PRB)的肿瘤抑制活性已得到很好的证实，因为视网膜母细胞瘤基因的突变与多种癌症有关。PRb对肿瘤的抑制部分依赖于它在分化中的作用，这在很大程度上是未知的。最近，Ewen实验室发现Rb基因作用于N-ras原癌基因的上游，调节小鼠的分化。此外，Rb和N-ras杂合子的小鼠会患上经常转移的甲状腺腺瘤。这项建议将通过测量小鼠卵泡旁细胞(C细胞)的转移潜能来研究Rb和N-ras之间的遗传相互作用。N-ras缺失导致C细胞转移的途径尚不清楚，但人们认为C细胞转移的原因可能是发育中的Hox基因表达异常，导致C细胞在正常胚胎发育过程中发生迁移。为了了解pRb和N-ras在转移中的作用，我们将测定N-ras的剂量对pRb无合子转移瘤中Hox基因表达的影响。建立转移和胚胎发育之间的联系将是理解恶性肿瘤的有价值的一步。

DESCRIPTION (provided by applicant): The tumor suppression activity of the retinoblastoma protein (pRb) is well established, as mutations in the retinoblastoma gene are associated with a wide variety of cancers. Tumor suppression by pRb is partly dependent on its role in differentiation, which is largely uncharacterized. Recently, the Ewen laboratory has shown that the Rb gene acts upstream of the N-ras proto-oncogene to regulate differentiation in mice. Furthermore, mice that are heterozygous for both Rb and N-ras develop thyroid adenomas that frequently metastasize. This proposal will study the genetic interaction between Rb and N-ras in parafollicular cells (C cells) of mice by measuring their metastatic potential as phenotype. The pathway by which N-ras loss contributes to metastasis is unknown, but it is thought that the migration of C-cell metastases may arise from aberrant expression of developmental Hox genes that cause C-cell migration in normal embryonic development. To understand the role of pRb and N-ras in metastasis, the effect of N-ras dosage on hox gene expression in pRb nullizygous metastases will be determined. Making the link between metastasis and embryonic development would be a valuable step in understanding malignant cancers.