Molecular systems biology of Sic1 in yeast cell cycle regulation through multiscale modeling

Adv Exp Med Biol. 2012;736:135-67. doi: 10.1007/978-1-4419-7210-1_7.

Abstract

Cell cycle control is highly regulated to guarantee the precise timing of events essential for cell growth, i.e., DNA replication onset and cell division. Failure of this control plays a role in cancer and molecules called cyclin-dependent kinase (Cdk) inhibitors (Ckis) exploit a critical function in cell cycle timing. Here we present a multiscale modeling where experimental and computational studies have been employed to investigate structure, function and temporal dynamics of the Cki Sic1 that regulates cell cycle progression in Saccharomyces cerevisiae. Structural analyses reveal molecular details of the interaction between Sic1 and Cdk/cyclin complexes, and biochemical investigation reveals Sic1 function in analogy to its human counterpart p27(Kip1), whose deregulation leads to failure in timing of kinase activation and, therefore, to cancer. Following these findings, a bottom-up systems biology approach has been developed to characterize modular networks addressing Sic1 regulatory function. Through complementary experimentation and modeling, we suggest a mechanism that underlies Sic1 function in controlling temporal waves of cyclins to ensure correct timing of the phase-specific Cdk activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites / genetics
  • Cell Cycle / genetics*
  • Cell Cycle / physiology
  • Cyclin-Dependent Kinase Inhibitor Proteins / chemistry
  • Cyclin-Dependent Kinase Inhibitor Proteins / genetics*
  • Cyclin-Dependent Kinase Inhibitor Proteins / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27 / chemistry
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Cyclin-Dependent Kinases / chemistry
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / chemistry
  • Cyclins / genetics
  • Cyclins / metabolism
  • Gene Regulatory Networks
  • Humans
  • Models, Genetic*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Systems Biology / methods*
  • Time Factors

Substances

  • Cyclin-Dependent Kinase Inhibitor Proteins
  • Cyclins
  • SIC1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases