Acetylation-dependent oncogenic activity of metastasis-associated protein 1 co-regulator.

• High expression of metastasis-associated protein 1 co-regulator (MTA1), a component of the nuclear remodelling and histone deacetylase complex, has been associated with human tumours. However, the precise role of MTA1 in tumorigenesis remains unknown. In this study, we show that induced levels of MTA1 are sufficient to transform Rat1 fibroblasts and that the transforming potential of MTA1 is dependent on its acetylation at Lys626. Underlying mechanisms of MTA1-mediated transformation include activation of the Ras-Raf pathway by MTA1 but not by acetylation-inactive MTA1; this was due to the repression of Galphai2 transcription, which negatively influences Ras activation. We observed that acetylated MTA1-histone deacetylase (HDAC) interaction was required for the recruitment of the MTA1-HDAC complex to the Galphai2 regulatory element and consequently for the repression of Galphai2 transcription and expression leading to activation of the Ras-Raf pathway. The findings presented in this study provide for the first time--to the best of our knowledge--evidence of acetylation-dependent oncogenic activity of a cancer-relevant gene product.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

Acetylation

Animals

Cell Line

Cell Movement

Cell Transformation

Neoplastic

Female

Fibroblasts

cytology

physiology

GTP-Binding Protein alpha Subunit

Gi2

genetics

metabolism

Gene Expression Regulation

Neoplastic

Histone Deacetylases

genetics

metabolism

Humans

Lysine

metabolism

Mice

Mice

Nude

Neoplasms

Experimental

Oncogenes

Repressor Proteins

genetics

metabolism

Transcription

Genetic

Transplantation

Heterologous

ras Proteins

genetics

metabolism

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)