Cajone F, Sherbet G V
Institute of General Pathology, University of Milan, Centro di Studio sulla Patologia Cellulare-C.N.R, Italy.
Clin Exp Metastasis. 1999;17(10):865-71. doi: 10.1023/a:1006778804532.
S100A4 is a cell proliferation- and cancer metastasis-related gene. Previous studies have shown that over-expression of S100A4 drives the cells into the S-phase of the cell cycle, with concomitant enhancement of p53 detection. This has led to the postulate that S100A4 could be controlling cell cycle progression by sequestering p53 and abrogating its G1-S checkpoint control. Cells induced by S100A4 to enter the S-phase do successfully negotiate the G2-M checkpoint control. Here we show that S100A4 is also involved in the regulation of control at this checkpoint. Stathmin is known to be associated, together with p53 in controlling G2-M transition. We present evidence that the expression of S100A4 and stathmin genes is up regulated in exponentially growing HeLa cells. They are down regulated in parallel when cell proliferation is inhibited by hyperthermia and 4-hydroxynonenal (4-HNE). We postulate that S100A4 might directly induce stathmin up regulation to enable cells to enter into mitosis. Since wild-type p53 is known to down regulate stathmin expression, we further postulate this might also involve S100A4-mediated sequestration of p53. The expression of heme oxygenase (HO-1), a stress-response protein, has been used to monitor effects of hyperthermia, 12-O-tetradecanoly phorbol 13-acetate (TPA) and 4-HNE. All these treatments induced HO-1 and also when cells growing in serum-deficiency were restored with full serum. HO-1 induction occurred irrespective of S100A4 expression status. HO-1 gene has responsive elements for many angiogenic agents and induces marked neovascularisation of tumours. We suggest therefore that S100A4 may not possess angiogenic properties.
S100A4是一种与细胞增殖和癌症转移相关的基因。先前的研究表明，S100A4的过表达会促使细胞进入细胞周期的S期，同时增强p53的检测信号。这导致了一种假设，即S100A4可能通过隔离p53并废除其G1-S期检查点控制来控制细胞周期进程。由S100A4诱导进入S期的细胞确实成功通过了G2-M期检查点控制。在此我们表明，S100A4也参与了这一检查点的调控。已知Stathmin与p53一起参与控制G2-M期转换。我们提供的证据表明，在指数生长的HeLa细胞中，S100A4和Stathmin基因的表达上调。当细胞增殖受到热疗和4-羟基壬烯醛（4-HNE）抑制时，它们会同时下调。我们推测，S100A4可能直接诱导Stathmin上调，以使细胞进入有丝分裂。由于已知野生型p53会下调Stathmin的表达，我们进一步推测这也可能涉及S100A4介导的p53隔离。血红素加氧酶（HO-1）是一种应激反应蛋白，其表达已被用于监测热疗、12-O-十四烷酰佛波醇-13-乙酸酯（TPA）和4-HNE的作用。所有这些处理都诱导了HO-1的表达，当血清缺乏的细胞恢复完全血清培养时也会诱导HO-1表达。HO-1的诱导与S100A4的表达状态无关。HO-1基因具有许多血管生成因子的反应元件，并可诱导肿瘤显著的新生血管形成。因此我们认为，S100A4可能不具有血管生成特性。
