Time-resolved human kinome RNAi screen identifies a network regulating mitotic-events as early regulators of cell proliferation

PLoS One. 2011;6(7):e22176. doi: 10.1371/journal.pone.0022176. Epub 2011 Jul 13.

Abstract

Analysis of biological processes is frequently performed with the help of phenotypic assays where data is mostly acquired in single end-point analysis. Alternative phenotypic profiling techniques are desired where time-series information is essential to the biological question, for instance to differentiate early and late regulators of cell proliferation in loss-of-function studies. So far there is no study addressing this question despite of high unmet interests, mostly due to the limitation of conventional end-point assaying technologies. We present the first human kinome screen with a real-time cell analysis system (RTCA) to capture dynamic RNAi phenotypes, employing time-resolved monitoring of cell proliferation via electrical impedance. RTCA allowed us to investigate the dynamics of phenotypes of cell proliferation instead of using conventional end-point analysis. By introducing data transformation with first-order derivative, i.e. the cell-index growth rate, we demonstrate this system suitable for high-throughput screenings (HTS). The screen validated previously identified inhibitor genes and, additionally, identified activators of cell proliferation. With the information of time kinetics available, we could establish a network of mitotic-event related genes to be among the first displaying inhibiting effects after RNAi knockdown. The time-resolved screen captured kinetics of cell proliferation caused by RNAi targeting human kinome, serving as a resource for researchers. Our work establishes RTCA technology as a novel robust tool with biological and pharmacological relevance amenable for high-throughput screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects
  • Enzyme Assays
  • Gene Knockdown Techniques
  • HeLa Cells
  • High-Throughput Screening Assays / methods*
  • Humans
  • Mitosis* / drug effects
  • Mitosis* / genetics
  • Phenotype
  • Phosphotransferases / antagonists & inhibitors
  • Phosphotransferases / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • RNA Interference*
  • RNA, Small Interfering / metabolism
  • Signal Transduction* / drug effects
  • Single-Cell Analysis
  • Time Factors

Substances

  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Phosphotransferases