Ahnak functions as a tumor suppressor via modulation of TGFβ/Smad signaling pathway

Oncogene. 2014 Sep 18;33(38):4675-84. doi: 10.1038/onc.2014.69. Epub 2014 Mar 24.

Abstract

We provide detailed mechanisms of Ahnak-mediated potentiation of transforming growth factor β (TGFβ) signaling, which leads to a negative regulation of cell growth. We show that Smad3 interacts with Ahnak through MH2 domain and that Ahnak stimulates Smad3 localization into nucleus leading to potentiating TGFβ-induced transcriptional activity of R-Smad. Moreover, overexpression of Ahnak resulted in growth retardation and cell cycle arrest through downregulation of c-Myc and cyclin D1/D2. We describe results from analyses of Ahnak(-/-) mouse model expressing middle T antigen in a mammary gland-specific manner (MMTV(Tg/+)Ahnak(-/-)), which showed significantly progressed hyperplasia of mammary glands compared with MMTV(Tg/+)Ahnak(+/+). Finally, we screened multiple human breast cancer tissues and showed that the expression of Ahnak in cancer tissues is lower than that in control tissues by 50%. Taken together, these data indicate that Ahnak mediates a negative regulation of cell growth and acts as novel tumor suppressor through potentiation of TGFβ signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Cycle Checkpoints
  • Cell Proliferation
  • Chlorocebus aethiops
  • Female
  • Humans
  • Male
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • NIH 3T3 Cells
  • Neoplasm Proteins / physiology*
  • Neoplasm Transplantation
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction
  • Smad Proteins / metabolism*
  • Transforming Growth Factor beta / physiology
  • Tumor Suppressor Proteins / physiology

Substances

  • Ahnak protein, mouse
  • Membrane Proteins
  • Neoplasm Proteins
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Transforming Growth Factor beta
  • Tumor Suppressor Proteins
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I