title: Autoregulation and heterogeneity in expression of human Cripto-1.
abstract: Cripto-1 (CR-1) is involved in various processes in embryonic development and cancer. Multiple pathways regulate CR-1 expression. Our present work demonstrates a possible positive feedback circuit where CR-1 induces its own expression. Using U-87 MG cells treated with exogenous CR-1, we show that such induction involves ALK4/SMAD2/3 pathway. Stochasticity in gene expression gives rise to heterogeneity in expression in genetically identical cells. Positive feedback increases such heterogeneity and often gives rise to two subpopulations of cells, having higher and lower expression of a gene. Using flow cytometry, we show that U-87 MG cells have a minuscule subpopulation with detectable expression of CR-1. Induction of CR-1 expression, by exogenous CR-1, increases the size of this CR-1 positive subpopulation. However, even at very high dose, most of the cells remain CR-1 negative. We show that population behavior of CR-1 induction has a signature similar to bimodal expression expected in a transcriptional circuit with positive feedback. We further show that treatment of U-87 MG cells with CR-1 leads to higher expression of drug efflux protein MDR-1 in the CR-1 positive subpopulation, indicating correlated induction of these two proteins. Positive feedback driven heterogeneity in expression of CR-1 may play crucial role in phenotypic diversification of cancer cells.
authors: Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati, India.
authors: Pojul
authors: P
authors: Loying
authors: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
authors: Janvie
authors: J
authors: Manhas
authors: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
authors: Sudip
authors: S
authors: Sen
authors: Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati, India.
authors: Biplab
authors: B
authors: Bose
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D030201:Activin Receptors, Type I / Q000378:metabolism; D000704:Analysis of Variance; D015153:Blotting, Western; D045744:Cell Line, Tumor; D025461:Feedback, Physiological / Q000502:physiology*; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; C070636:TDGF1 protein, human; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I