Oncogene-induced up-regulation of Caco-2 cell proliferation involves IGF-II gene activation through a protein kinase C-mediated pathway

Oncogene. 1998 Aug 20;17(7):877-87. doi: 10.1038/sj.onc.1202013.


We previously reported that ras and polyoma middle T (PyMT), a constitutive activator of the src protooncogene product, up-regulated Caco-2 cell proliferation along with protein kinase C (PKC) alpha expression and PKC activity. We aimed to investigate whether oncogene-induced up-regulation of Caco-2 cell proliferation involved stimulation of the autocrine IGF-II/IGF-I receptor (IGFIR) loop described in these cells and if so, to analyse the role of overexpressed and activated PKC. Compared with control vector transfected Caco-2 cells, ras- and PyMT-transfected cells exhibited increased expression of the 6.0 and 4.8 kb IGF-II transcripts. This was due to increased activity of the P3 and P4 promoters of the IGF-II gene which correlated with increased expression and DNA-binding activity of Sp1, a transcription factor interacting with several specific sites in P3 and P4 promoters. Oncogene-transfected cells displayed enhanced autocrine IGF-II production, which was fully responsible for the oncogene-induced increase in their proliferation since this increase was blunted by anti-human IGF-II and IGF1R (alphaIR3) antibodies. PKC mediated oncogene activation of the IGF-II gene presumably through action on Sp1 since (i) PKC activation by phorbol 12-myristate 13-acetate increased Sp1 expression, P3 and P4 activity and IGF-II mRNA in control but not in oncogene-transfected cells; and (ii) PKC inhibition by the PKC inhibitor Gö6976 reduced Sp1, P3 and P4 activity and IGF-II mRNA in all three cell lines. This is the first evidence that ras- and PyMT/src oncogenes up-regulate Caco-2 cell proliferation through a PKC-mediated pathway which stimulates IGF-II gene transcription and thereby increases autocrine IGF-II production. The mechanisms underlying IGF-II gene activation by PKC most probably involve action on Sp1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Antigens, Polyomavirus Transforming / biosynthesis
  • Antigens, Polyomavirus Transforming / genetics*
  • Caco-2 Cells
  • Cell Division / genetics*
  • Gene Expression Regulation, Neoplastic*
  • Genes, ras*
  • Humans
  • Insulin-Like Growth Factor Binding Proteins / biosynthesis
  • Insulin-Like Growth Factor Binding Proteins / genetics
  • Insulin-Like Growth Factor II / biosynthesis
  • Insulin-Like Growth Factor II / genetics*
  • Insulin-Like Growth Factor II / physiology
  • Oncogenes*
  • Protein Kinase C / metabolism*
  • Receptor, IGF Type 1 / physiology
  • Signal Transduction
  • Sp1 Transcription Factor / genetics
  • Sp1 Transcription Factor / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription, Genetic*
  • Transcriptional Activation
  • Transfection


  • Antibodies, Monoclonal
  • Antigens, Polyomavirus Transforming
  • Insulin-Like Growth Factor Binding Proteins
  • Sp1 Transcription Factor
  • Insulin-Like Growth Factor II
  • Receptor, IGF Type 1
  • Protein Kinase C
  • Tetradecanoylphorbol Acetate