Cell Growth Inhibiton and Estrogen Action

Summary

Principal Investigator: Andrea Reyna
Abstract: DESCRIPTION: (provided by the applicant) A long-range goal of this research is to define the role of MeHPLA and nuclear type II sites in normal and malignant cell proliferation. The identification of MeHPLA as a ligand for type II sites which controls cell growth led to the development of MeHPLA-related compounds with antiproliferative activities and potential for the treatment of benign prostatic hyperplasia, endometriosis, breast and prostatic cancer. We recently identified the nuclear type II binding site as histone H4. This exciting discovery targets very specific genomic pathways for regulation by MeHPLA and related-compounds including bioflavonoids and phytoestrogens. These compounds bind to type II sites (histone H4) with high affinity and have classically been defined as antioxidants that scavage free radicals. Our recent data indicate very specific regulation of gene transcription at the level of chromatin structure and function by type II site (histone H4) ligands. Histone acetylation is temporally and functionally coupled to DNA replication and gene expression in experimental systems including uterus and cancer cells. We propose that MeHPLA and related compounds control normal and malignant cell proliferation by modulating chromatin acetylation patterns and core nucleosome unwinding by binding to histone H4. We will assess hormonal (estrogen, progesterone) modulation of histone H4 gene expression (mRNA and protein), ligand binding activity and cell proliferation in rat uterus and in ER-dependent (MCF-7 cells) and ER-independent (MDA-MD-231) breast cancer cells in vitro and when grown in nude mice (Specific Aim 1). Potential involvement of histones H1, H2A, H2B and H3 in ligand binding to histone H4 will be studied (Specific Aim 2). The identity of the ligand binding domain(s) on histone H4 by will be determined by protein sequencing and site directed mutagenesis studies (Specific Aim 3). Effects of MeHPLA and related histone H4 ligands on chromatin structure, histone acetylation, and steroid hormone-dependent chromatin remodeling and gene transcription in a cell free system (Specific Aim 4) will be assessed. Estrogen, antiestrogen and MeHPLArelated compound effect on the acetylation of histone H4 (or other histones), specific gene (cyclin Dl and p21) transcription and expression and cell proliferation (cell cycle transcition, etc.) in estrogen-dependent and estrogen-independent breast cancer cells in vitro and in vivo (Specific Aim 5) will be evaluated. The proposed studies should precisely define specific effects of MeHPLA and bioflavonoids on chromatin structure and function, growth related gene transcription and cellular proliferation in normal and malignant cells.
Funding Period: 1983-08-01 - 2007-07-31
more information: NIH RePORT

Top Publications

  1. pmc Luteolin and gefitinib regulation of EGF signaling pathway and cell cycle pathway genes in PC-3 human prostate cancer cells
    Barry M Markaverich
    Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States
    J Steroid Biochem Mol Biol 122:219-31. 2010
  2. pmc Regulation of cell cycle and RNA transcription genes identified by microarray analysis of PC-3 human prostate cancer cells treated with luteolin
    Kevin Shoulars
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    J Steroid Biochem Mol Biol 118:41-50. 2010
  3. pmc Regulation of the nitric oxide pathway genes by tetrahydrofurandiols: microarray analysis of MCF-7 human breast cancer cells
    Kevin Shoulars
    Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Room 405A, Houston, TX 77030, USA
    Cancer Lett 264:265-73. 2008
  4. pmc Tetrahydrofurandiol stimulation of phospholipase A2, lipoxygenase, and cyclooxygenase gene expression and MCF-7 human breast cancer cell proliferation
    Barry M Markaverich
    Department of Molecular and Cellular Biology, Baylor Colloege of Medicine, Houston, TX 77030, USA
    Environ Health Perspect 115:1727-31. 2007
  5. pmc Tetrahydrofurandiols (THF-diols), leukotoxindiols (LTX-diols), and endocrine disruption in rats
    Barry M Markaverich
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
    Environ Health Perspect 115:702-8. 2007
  6. ncbi Nuclear type II [3H]estradiol binding site ligands: inhibition of ER-positive and ER-negative cell proliferation and c-Myc and cyclin D1 gene expression
    Barry M Markaverich
    Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
    Steroids 71:865-74. 2006
  7. ncbi Reconstitution of the type II [3H]estradiol binding site with recombinant histone H4
    Kevin Shoulars
    Department of Molecular and Cellular Biology, Baylor College of Medicine One Baylor Plaza, Houston, TX 77030, USA
    J Steroid Biochem Mol Biol 99:1-8. 2006
  8. pmc Leukotoxin diols from ground corncob bedding disrupt estrous cyclicity in rats and stimulate MCF-7 breast cancer cell proliferation
    Barry M Markaverich
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
    Environ Health Perspect 113:1698-704. 2005
  9. ncbi Disruption of male sexual behavior in rats by tetrahydrofurandiols (THF-diols)
    Shaila K Mani
    Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
    Steroids 70:750-4. 2005
  10. ncbi Nuclear type II [3H]estradiol binding sites: a histone H3-H4 complex
    Kevin Shoulars
    Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 3498, USA
    J Steroid Biochem Mol Biol 96:19-30. 2005

Scientific Experts

  • Andrea Reyna
  • Kevin Shoulars
  • Barry M Markaverich
  • Trellis Thompson
  • John Sharp
  • Jan Crowley
  • Shaila Mani
  • Jan R Crowley
  • Shaila K Mani
  • Mary A Alejandro
  • Mary Vijjeswarapu
  • Mary Rodriguez
  • Wendy Portillo
  • Mary Rodriquez
  • Mary Alejandro
  • John Turk
  • Mary Ann Alejandro
  • Nancy Casajuna

Detail Information

Publications11

  1. pmc Luteolin and gefitinib regulation of EGF signaling pathway and cell cycle pathway genes in PC-3 human prostate cancer cells
    Barry M Markaverich
    Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States
    J Steroid Biochem Mol Biol 122:219-31. 2010
    ....
  2. pmc Regulation of cell cycle and RNA transcription genes identified by microarray analysis of PC-3 human prostate cancer cells treated with luteolin
    Kevin Shoulars
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    J Steroid Biochem Mol Biol 118:41-50. 2010
    ..Taken together, the data suggest that type II ligands inhibit cell growth and proliferation through epigenetic control of key genes involved in cell cycle progression and RNA transcription...
  3. pmc Regulation of the nitric oxide pathway genes by tetrahydrofurandiols: microarray analysis of MCF-7 human breast cancer cells
    Kevin Shoulars
    Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Room 405A, Houston, TX 77030, USA
    Cancer Lett 264:265-73. 2008
    ..These findings are consistent with the well-known involvement of NOP genes in cell proliferation and sexual behavior...
  4. pmc Tetrahydrofurandiol stimulation of phospholipase A2, lipoxygenase, and cyclooxygenase gene expression and MCF-7 human breast cancer cell proliferation
    Barry M Markaverich
    Department of Molecular and Cellular Biology, Baylor Colloege of Medicine, Houston, TX 77030, USA
    Environ Health Perspect 115:1727-31. 2007
    ..Synthetic THF-diols inhibited rat male and female sexual behavior at oral concentrations of 0.5-1 ppm, and stimulated MCF-7 human breast cancer cell proliferation in vitro...
  5. pmc Tetrahydrofurandiols (THF-diols), leukotoxindiols (LTX-diols), and endocrine disruption in rats
    Barry M Markaverich
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
    Environ Health Perspect 115:702-8. 2007
    ..The authentic compounds blocked sexual behavior in male rats and estrous cyclicity in female rats at oral doses of 2 ppm...
  6. ncbi Nuclear type II [3H]estradiol binding site ligands: inhibition of ER-positive and ER-negative cell proliferation and c-Myc and cyclin D1 gene expression
    Barry M Markaverich
    Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
    Steroids 71:865-74. 2006
    ..al, J Steroid Biochem. Mol. Biol. 96: 19-30, 2005)...
  7. ncbi Reconstitution of the type II [3H]estradiol binding site with recombinant histone H4
    Kevin Shoulars
    Department of Molecular and Cellular Biology, Baylor College of Medicine One Baylor Plaza, Houston, TX 77030, USA
    J Steroid Biochem Mol Biol 99:1-8. 2006
    ....
  8. pmc Leukotoxin diols from ground corncob bedding disrupt estrous cyclicity in rats and stimulate MCF-7 breast cancer cell proliferation
    Barry M Markaverich
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
    Environ Health Perspect 113:1698-704. 2005
    ..8 mg/kg body weight/day) disrupted estrous cyclicity in female rats. The LTX-diols did not disrupt male sexual behavior, suggesting that sex differences exist in response to these endocrine-disruptive agents...
  9. ncbi Disruption of male sexual behavior in rats by tetrahydrofurandiols (THF-diols)
    Shaila K Mani
    Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
    Steroids 70:750-4. 2005
    ..These findings suggest that the THF-diols modulate hypothalamo-pituitary axis to regulate steroid hormone-dependent male sexual behavior...
  10. ncbi Nuclear type II [3H]estradiol binding sites: a histone H3-H4 complex
    Kevin Shoulars
    Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 3498, USA
    J Steroid Biochem Mol Biol 96:19-30. 2005
    ....