Phosphoinositide-3-kinase signaling controls S-phase kinase-associated protein 2 transcription via E2F1 in pancreatic ductal adenocarcinoma cells

Cancer Res. 2007 May 1;67(9):4149-56. doi: 10.1158/0008-5472.CAN-06-4484.


The phosphoinositide-3-kinase (PI3K)/AKT signaling pathway controls fundamental processes of cancer cell biology like proliferation and cell survival. The PI3K/AKT pathway is activated in pancreatic ductal adenocarcinoma (PDAC) cells. The molecular mechanisms linking PI3K signaling to the cell cycle machinery in PDAC cells are not investigated in detail. Using the PI3K inhibitor Ly294002 as well as small interfering RNA targeting AKT1 expression, we show that PI3K controls the proliferation and G(1) phase progression of PDAC cells. Gene profiling revealed several important regulators of G(1)-S phase progression controlled by PI3K signaling like p21(Cip1), S-phase kinase-associated protein 2 (SKP2), CDC25a, cyclin A, cyclin D2, CDK2, and cyclin E. We show that the F-box protein SKP2, an oncogene up-regulated in PDAC, is transcriptionally regulated by the PI3K/AKT1 pathway in PDAC cells. At the molecular level, the control of the SKP2 gene by PI3K is due to the regulation of E2F1 binding to the proximal SKP2 gene promoter. The complex and profound connection of PI3K/AKT1 signaling to the cell cycle qualifies this pathway as a suitable target for therapeutic intervention in PDAC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Pancreatic Ductal / enzymology
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Cell Cycle / physiology
  • Cell Growth Processes / physiology
  • Chromones / pharmacology
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism*
  • G1 Phase / physiology
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Morpholines / pharmacology
  • Pancreatic Neoplasms
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Small Interfering
  • S Phase / physiology
  • S-Phase Kinase-Associated Proteins / biosynthesis*
  • S-Phase Kinase-Associated Proteins / genetics
  • Signal Transduction
  • Transcription, Genetic


  • Chromones
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • RNA, Messenger
  • RNA, Small Interfering
  • S-Phase Kinase-Associated Proteins
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Proto-Oncogene Proteins c-akt