Stathmin is involved in S100A4-mediated regulation of cell cycle progression

S100A4 is a cell proliferation- and cancer metastasis-related gene. Previou s studies have shown that over-expression of S100A4 drives the cells into t he 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 G(1)-S checkpoint contr ol. Cells induced by S100A4 to enter the S-phase do successfully negotiate the G(2)-M checkpoint control. Here we show that S100A4 is also involved in the regulation of control at this checkpoint. Stathmin is known to be asso ciated, together with p53 in controlling G(2)-M transition. We present evid ence that the expression of S100A4 and stathmin genes is up regulated in ex ponentially growing HeLa cells. They are down regulated in parallel when ce ll proliferation is inhibited by hyperthermia and 4-hydroxynonenal (4-HNE). We postulate that S100A4 might directly induce stathmin up regulation to e nable cells to enter into mitosis. Since wild-type p53 is known to down reg ulate stathmin expression, we further postulate this might also involve S10 0A4-mediated sequestration of p53. The expression of heme oxygenase (HO-1), a stress-response protein, has been used to monitor effects of hyperthermi a, 12-O-tetradecanoly phorbol 13-acetate (TPA) and 4-HNE. All these treatme nts induced HO-1 and also when cells growing in serum-deficiency were resto red with full serum. HO-1 induction occurred irrespective of S100A4 express ion status. HO-1 gene has responsive elements for many angiogenic agents an d induces marked neovascularisation of tumours. We suggest therefore that S 100A4 may not possess angiogenic properties.