External control of Her2 expression and cancer cell growth by targeting a Ras-linked coactivator.
Overproduction of the Her2 oncoprotein has been found in approximately 30% of breast tumors, and patients who have Her2 excesses typically have more aggressive disease. Here we show that the expression of the Her2 gene can be decreased by inhibiting the interaction of the two cancer-linked proteins, DRIP130/CRSP130/Sur-2 (a Ras-linked subunit of human mediator complexes) and ESX (an epithelial-restricted transcription factor). Disruption of the interaction by a short cell-permeable peptide reduced the expression of the Her2 gene and specifically impaired the growth and viability of Her2-overexpressing breast cancer cells. The association of ESX with DRIP130 is mediated by a small hydrophobic face of an 8-aa helix in ESX, suggesting a therapeutic approach to incapacitating the Her2 gene by small organic molecules.
Asada
Shinichi
S
The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Choi
Yongmun
Y
Yamada
Masaki
M
Wang
Shao-Chun
SC
Hung
Mien-Chie
MC
Qin
Jun
J
Uesugi
Motonari
M
D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D018734:Genes, erbB-2 / Q000235:genetics*; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D009682:Magnetic Resonance Spectroscopy; D056892:Mediator Complex; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism*
D005982:Glutathione Transferase; D056892:Mediator Complex; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D018631:ras Proteins; C492159:MED23 protein, human