Major vault protein, in concert with constitutively photomorphogenic 1, negatively regulates c-Jun-mediated activator protein 1 transcription in mammalian cells.
Constitutively photomorphogenic 1 (COP1), a RING finger ubiquitin ligase with substrates including c-Jun and p53, was recently found to be overexpressed in a number of breast and ovarian tumor samples. In addition to its E3 activity, COP1 was also shown to be able to inhibit activator protein 1 (AP-1) transcription. Through an affinity purification method, we have identified major vault protein (MVP) as a novel interacting partner for COP1 in mammalian cells. MVP, also known as lung resistance protein, is the main component of a ribonucleoprotein organelle called vault, and has been implicated in multiple drug resistance in many cancer cell lines and primary tumor samples. The interaction between COP1 and MVP is detectable at the endogenous level and occurs mostly in the cytoplasm. Similar to COP1, MVP inhibits c-Jun accumulation and AP-1 transcription activity. MVP knockout or knockdown cells contain elevated amount of c-Jun and increased AP-1 transcription activity. UV irradiation enhances MVP tyrosine phosphorylation, causes dissociation of COP1 from MVP, and alleviates the inhibitory activity of MVP on AP-1 transcription. Taken together, we propose that MVP, most likely through its interaction with COP1, suppresses c-Jun-mediated AP-1 transcription under unstressed conditions, thereby preventing cells from undergoing stress response.
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520-8104, USA.
Chunling
C
Yi
Shuting
S
Li
Xishu
X
Chen
Erik A C
EA
Wiemer
Jian
J
Wang
Ning
N
Wei
Xing Wang
XW
Deng
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014466:Ultraviolet Rays; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000099187:Major Vault Protein
D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D044767:Ubiquitin-Protein Ligases; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C471981:COP1 protein, human