The APC tumor suppressor controls entry into S-phase through its ability to regulate the cyclin D/RB pathway

Gastroenterology. 2002 Sep;123(3):751-63. doi: 10.1053/gast.2002.35382.

Abstract

Background & aims: APC gene mutation is an early alteration in most colorectal tumors. In an attempt to determine its role in tumor development, we asked whether reintroducing wild-type APC into colorectal cancer cells with mutant APC affected cell cycle progression.

Methods: Using transient transfection, a plasmid containing the APC complementary DNA and DNA encoding the green fluorescent protein was expressed in SW480 cells. In addition, several other constructs were co-expressed with APC to determine their combined effects.

Results: We report that colorectal cancer cell lines transfected with wild-type APC arrest in the G(1)- phase of the cell cycle and that this arrest is abrogated by cotransfecting constitutively active beta-catenin or cyclin D1 and cMYC together. This APC-induced cell cycle arrest involves the disruption of beta-catenin-mediated transcription and depends on components of the G(1)/S regulatory machinery, as overexpression of E1a or E2F-1, -2, or -3 overrides the G(1) arrest. Consistent with this, APC transfection inhibits RB phosphorylation and reduces levels of cyclin D1.

Conclusions: Our results suggest that APC functions upstream of RB in the G(1)/S regulatory pathway, cyclin D1 and cMYC affect APC-mediated arrest equivalently to oncogenic beta-catenin, and most colon tumors disrupt control of G(1)/S progression by APC mutation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenovirus E2 Proteins / pharmacology
  • Cell Cycle / drug effects
  • Cyclin D1 / antagonists & inhibitors
  • Cyclin D1 / metabolism*
  • Cyclin D1 / pharmacology
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / pharmacology
  • Drug Combinations
  • G1 Phase / physiology
  • Genes, APC / physiology*
  • Genes, Tumor Suppressor / physiology*
  • Humans
  • Oncogenes / physiology
  • Phosphorylation
  • Proto-Oncogene Proteins c-myc / pharmacology
  • Retinoblastoma Protein / metabolism*
  • S Phase / physiology*
  • Trans-Activators / genetics
  • Trans-Activators / pharmacology
  • Transcription, Genetic / drug effects
  • Transfection
  • Tumor Cells, Cultured
  • beta Catenin

Substances

  • Adenovirus E2 Proteins
  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • Drug Combinations
  • Proto-Oncogene Proteins c-myc
  • Retinoblastoma Protein
  • Trans-Activators
  • beta Catenin
  • Cyclin D1