title: Effects of flavonoids on expression of genes involved in cell cycle regulation and DNA replication in human fibroblasts.
abstract: Flavonoids have been studied as potential agents in medicine for many years. Among them, genistein was found to be active in various biological systems, mainly in prevention of cancer. Our recent work supported the idea that genistein also impacts multiple cellular processes in healthy fibroblasts; however, its effects on cell cycle-related pathways remained to be elucidated. Thus, in this work, high throughput screening with microarrays coupled to real-time quantitative Reverse Transcription PCR analyses was employed to study the changes in expression of key genes associated with cell cycle regulation and/or DNA replication in response to genistein, kaempferol, daidzein, and mixtures of genistein and either kaempferol or daidzein. Among them, genistein was found as the most significantly modulating, in a time- and dose-dependent manner, compound of activity of studied genes, whose products are involved in different phases of the cell cycle and/or in regulatory processes important for DNA replication and cell growth. It considerably reduced the efficiency of expression of genes coding for MCM2-7 and MCM10 helicases, as well as some other proteins involved in the S phase control. In addition, genistein caused cell cycle arrest in the G2/M phase, which was accompanied by activation of CDKN1A, CDKN1C, CDKN2A, CDKN2B, CDKN2C, and GADD45A genes, as well as down-regulation of several mRNAs specific for this stage, demonstrated by transcriptomic assessments. We believe that studies described in this paper will be helpful in elucidating molecular mechanisms of action of genistein as modulator of cell cycle and inhibitor of DNA replication in humans.
authors.affiliation: Laboratory of Molecular Biology (affiliated with the University of Gdańsk), Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Wita Stwosza 59, 80-308, Gdańsk, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Moskot
authors.forename: Joanna
authors.initials: J
authors.lastname: Jakóbkiewicz-Banecka
authors.forename: Elwira
authors.initials: E
authors.lastname: Smolińska
authors.forename: Ewa
authors.initials: E
authors.lastname: Piotrowska
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Węgrzyn
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gabig-Cimińska
mesh_terms: D002453:Cell Cycle / Q000187:drug effects*; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D044949:Kaempferols / Q000494:pharmacology; D064110:Minichromosome Maintenance Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D005419:Flavonoids; D007529:Isoflavones; D044949:Kaempferols; C489613:MCM10 protein, human; C004742:daidzein; C006552:kaempferol; D019833:Genistein; D064110:Minichromosome Maintenance Proteins