A retroviral expression system based on tetracycline-regulated tricistronic transactivator/repressor vectors for functional analyses of antiproliferative and toxic genes

Mol Cancer Ther. 2006 Aug;5(8):1927-34. doi: 10.1158/1535-7163.MCT-05-0500.

Abstract

Establishment of stably transfected mammalian cells with conditional expression of antiproliferative or proapoptotic proteins is often hampered by varying expression within bulk-selected cells and high background in the absence of the inducing drug. To overcome such limitations, we designed a gene expression system that transcribes the tetracycline-dependent rtTA2-M2-activator, TRSID-silencer, and selection marker as a tricistronic mRNA from a single retroviral vector. More than 92% of bulk-selected cells expressed enhanced green fluorescent protein or luciferase over more than three orders of magnitude in an almost linear, dose-dependent manner. To functionally test this system, we studied how dose-dependent expression of p27(Kip1) affects proliferation and viability of SH-EP neuroblastoma cells. Low to moderate p27(Kip1) expression caused transient G(0)-G(1) accumulation without reduced viability, whereas high p27(Kip1) levels induced significant apoptosis after 72 hours. This proves that this expression system allows concentration-dependent analysis of gene function and implicates p27(Kip1) as a critical regulator of both proliferation and apoptosis in SH-EP neuroblastoma cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics*
  • Cell Cycle / genetics
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p27
  • Doxycycline / pharmacology
  • Gene Expression Profiling / methods*
  • Genetic Vectors / genetics*
  • Green Fluorescent Proteins / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Neuroblastoma / genetics
  • Neuroblastoma / pathology
  • Repressor Proteins / drug effects
  • Repressor Proteins / genetics*
  • Retroviridae / genetics*
  • Tetracycline / pharmacology*
  • Trans-Activators / drug effects
  • Trans-Activators / genetics*
  • Transfection
  • Tristetraprolin / drug effects
  • Tristetraprolin / genetics
  • Tumor Cells, Cultured

Substances

  • CDKN1B protein, human
  • Intracellular Signaling Peptides and Proteins
  • Repressor Proteins
  • Trans-Activators
  • Tristetraprolin
  • Green Fluorescent Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Tetracycline
  • Doxycycline