Dominant-negative c-Jun (TAM67) target genes: HMGA1 is required for tumor promoter-induced transformation

Oncogene. 2004 May 27;23(25):4466-76. doi: 10.1038/sj.onc.1207581.


Activation of the transcription factor AP-1 (activator protein-1) is required for tumor promotion and maintenance of malignant phenotype. A number of AP-1-regulated genes that play a role in tumor progression have been identified. However, AP-1-regulated genes driving tumor induction are yet to be defined. Previous studies have established that expression of a dominant-negative c-Jun (TAM67) inhibits phorbol 12-tetradecanoyl-13-acetate (TPA)-induced AP-1 transactivation as well as transformation in mouse epidermal JB6/P+ cells and tumor promotion in mouse skin carcinogenesis. In this study, we utilized the tumor promotion-sensitive JB6/P+ cells to identify AP-1-regulated TAM67 target genes and to establish causal significance in transformation for one target gene. A 2700 cDNA microarray was queried with RNA from TPA-treated P+ cells with or without TAM67 expression. Under conditions in which TAM expression inhibited TPA-induced transformation, microarray analysis identified a subset of six genes induced by TPA and suppressed by TAM67. One of the identified genes, the high-mobility group protein A1 (Hmga1) is induced by TPA in P+, but not in transformation-resistant P cells. We show that TPA induction of the architectural transcription factor HMGA1 is inhibited by TAM67, is extracellular-signal-regulated kinase (ERK)-activation dependent, and is mediated by AP-1. HMGA1 antisense construct transfected into P+ cells blocked HMGA1 protein expression and inhibited TPA-induced transformation indicating that HMGA1 is required for transformation. HMGA1 is not however sufficient as HMGA1a or HMGA1b overexpression did not confer transformation sensitivity on P- cells. Although HMGA1 expression is ERK dependent, it is not the only ERK-dependent event required for transformation because it does not suffice to rescue ERK-deficient P- cells. Our study shows (a) TAM 67 when it inhibits AP-1 and transformation, targets a relatively small number of genes; (b) HMGA1, a TAM67 target gene, is causally related to transformation and therefore a potentially important target for cancer prevention.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Butadienes / pharmacology
  • Cell Line / drug effects
  • Cell Line / metabolism
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics*
  • Clone Cells / drug effects
  • Clone Cells / metabolism
  • Cyclin D1 / biosynthesis
  • Cyclin D1 / genetics
  • DNA, Complementary / genetics
  • Disease Susceptibility
  • Epidermal Cells*
  • Epidermis / drug effects
  • Epidermis / metabolism
  • Gene Expression Profiling
  • Genes, jun / genetics*
  • HMGA1a Protein / physiology*
  • HMGA1b Protein / physiology*
  • MAP Kinase Kinase Kinase 1*
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Signaling System
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 1 / physiology
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / physiology
  • Nitriles / pharmacology
  • Oligonucleotide Array Sequence Analysis
  • Oligonucleotides, Antisense / pharmacology
  • Osteopontin
  • Proto-Oncogene Proteins c-jun / deficiency
  • Proto-Oncogene Proteins c-jun / physiology*
  • Sialoglycoproteins / biosynthesis
  • Sialoglycoproteins / genetics
  • Tetradecanoylphorbol Acetate / toxicity
  • Transcription Factor AP-1 / physiology
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / genetics*


  • Butadienes
  • DNA, Complementary
  • Nitriles
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins c-jun
  • Sialoglycoproteins
  • Spp1 protein, mouse
  • Transcription Factor AP-1
  • U 0126
  • Osteopontin
  • HMGA1b Protein
  • HMGA1a Protein
  • Cyclin D1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP Kinase Kinase Kinases
  • Map3k1 protein, mouse
  • Tetradecanoylphorbol Acetate