Li X, Drucker D J
Department of Clinical Biochemistry, University of Toronto, Ontario, Canada.
J Biol Chem. 1994 Mar 4;269(9):6263-6.
Neoplastic transformation may be associated with the development of paraneoplastic syndromes that complicate the management of patients with malignant disease. One of these syndromes, humoral hypercalcemia of malignancy, has been shown to be attributable to increased secretion of a parathyroid hormone-related peptide (PTHrP). The gene encoding PTHrP is expressed at low levels in a growth factor-dependent manner in normal tissues, and the mechanisms underlying selective tumor-associated induction of PTHrP gene expression remain unclear. Here we show that cellular transformation by the EJ-Ha-ras and v-src oncogenes is associated with a marked increase in PTHrP gene expression. Ha-ras- and v-src-transfected NRK 49F cells and ras-transfected RCB 2.2 cell lines secreted increased amounts of immunoreactive PTHrP. Northern blot analysis also demonstrated increased levels of PTHrP mRNA transcripts in oncogene-transfected stable cell lines. No significant change in the half-life of PTHrP mRNA transcripts was detected in Ha-ras- and v-src-transformed cells. In contrast, nuclear run-on assays demonstrated an increased rate of PTHrP gene transcription in oncogene-transformed cells. These observations demonstrate that the gene encoding PTHrP is a downstream target for ras and src, potentially providing a molecular basis for understanding the activation of PTHrP gene expression in malignancy-associated hypercalcemia.
肿瘤转化可能与副肿瘤综合征的发生有关，这会使恶性疾病患者的治疗变得复杂。其中一种综合征，即恶性肿瘤体液性高钙血症，已被证明是由于甲状旁腺激素相关肽（PTHrP）分泌增加所致。编码PTHrP的基因在正常组织中以生长因子依赖的方式低水平表达，而PTHrP基因表达的选择性肿瘤相关诱导的潜在机制仍不清楚。在此我们表明，EJ-Ha-ras和v-src癌基因介导的细胞转化与PTHrP基因表达的显著增加有关。Ha-ras和v-src转染的NRK 49F细胞以及ras转染的RCB 2.2细胞系分泌的免疫反应性PTHrP量增加。Northern印迹分析也表明癌基因转染的稳定细胞系中PTHrP mRNA转录本水平增加。在Ha-ras和v-src转化的细胞中未检测到PTHrP mRNA转录本半衰期的显著变化。相反，核转录分析表明癌基因转化细胞中PTHrP基因转录速率增加。这些观察结果表明，编码PTHrP的基因是ras和src的下游靶点，这可能为理解恶性肿瘤相关高钙血症中PTHrP基因表达的激活提供分子基础。
