title: Stathmin is involved in S100A4-mediated regulation of cell cycle progression.
abstract: 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.
authors.affiliation: Institute of General Pathology, University of Milan, Centro di Studio sulla Patologia Cellulare-C.N.R, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Cajone
authors.forename: G V
authors.initials: GV
authors.lastname: Sherbet
mesh_terms: D016475:3T3 Cells / Q000187:drug effects; D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005347:Fibroblasts; D005786:Gene Expression Regulation / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D006801:Humans; D006979:Hyperthermia, Induced; D051379:Mice; D008868:Microtubule Proteins; D010750:Phosphoproteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D050777:Stathmin; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000447:Aldehydes; D016895:Culture Media, Serum-Free; D008868:Microtubule Proteins; D010750:Phosphoproteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; C493995:STMN1 protein, human; D050777:Stathmin; C493994:Stmn1 protein, mouse; C077591:S100A4 protein, human; D006419:Heme Oxygenase (Decyclizing); C027576:4-hydroxy-2-nonenal; D013755:Tetradecanoylphorbol Acetate