ACTH promotion of p27(Kip1) induction in mouse Y1 adrenocortical tumor cells is dependent on both PKA activation and Akt/PKB inactivation

Biochemistry. 2002 Aug 6;41(31):10133-40. doi: 10.1021/bi0258086.


Here we report antimitogenic mechanisms activated by the adrenocorticotropic hormone (ACTH) in the mouse Y1 adrenocortical tumor cell line. ACTH receptors activate the Galphas/adenylate cyclase cAMP/PKA pathway to promote dephosphorylation of Akt/PKB enzymes, leading to induction of the cyclin-dependent kinases' (CDKs) inhibitor p27(Kip1). Y1 cells display high constitutive levels of phosphorylated Akt/PKB dependent on chronically elevated c-Ki-Ras.GTP and PI3K activity. Expression of the dominant negative mutant RasN17 in Y1 cells results in strong reduction of both c-Ki-Ras.GTP and phosphorylated Akt/PKB, which are restored by FGF2 treatments. Inhibitors of PI3K lead to rapid dephosphorylation of Akt/PKB and block phosphorylation of Akt/PKB promoted by FGF2. ACTH rapidly promotes dephosphorylation of Akt/PKB in Y1 adrenal cells, while constitutively high levels of c-Ki-Ras.GTP remain unchanged. ACTH and cAMP elevating agents fail to cause Akt/PKB dephosphorylation in PKA-deficient clonal mutants of Y1 cells. In addition, cholera toxin, forskolin, and 8BrcAMP all mimic ACTH, causing dephosphorylation of Akt/PKB in wild-type Y1 cells. ACTH is unable to prevent Akt/PKB phosphorylation, promoted by FGF2 in clonal lines of RasN17-Y1 transfectants displaying negligible levels of c-Ki-Ras.GTP. ACTH promotes strong p27(Kip1) protein induction in wild-type Y1 adrenocortical cells but not in PKA-deficient Y1-clonal mutants nor in RasN17-Y1 transfectants. PI3K inhibitors induce p27(Kip1) protein in all cells studied, i.e., wild type and transfectants. The inverse correlation between levels of phosphorylated Akt/PKB and of p27(Kip1) protein caused by ACTH suggests a novel antimitogenic pathway activated by ACTH and mediated by cAMP/PKA in the mouse Y1 adrenocortical tumor cell line.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Neoplasms / enzymology
  • Adrenal Cortex Neoplasms / metabolism*
  • Adrenocorticotropic Hormone / physiology*
  • Animals
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis*
  • Cyclins / genetics
  • Mice
  • Phosphorylation
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Tumor Cells, Cultured


  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Proto-Oncogene Proteins
  • Adrenocorticotropic Hormone
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Cyclic AMP-Dependent Protein Kinases