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

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

Author information

1
Department of Life Sciences and GT5 program, Ewha Womans University, Seoul, Korea.
2
Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
3
College of Pharmacy, Gachon University, Incheon, Korea.
4
Department of Surgery, School of Medicine, Seoul National University, Seoul, Korea.
5
Department of Obstetrics and Gynecology, Samsung Hospital, SungKyunKwan University, Seoul, Korea.

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.

PMID:
24662814
PMCID:
PMC4180639
DOI:
10.1038/onc.2014.69
[Indexed for MEDLINE]
Free PMC Article
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