期刊
EMBO JOURNAL
卷 22, 期 24, 页码 6471-6482出版社
WILEY
DOI: 10.1093/emboj/cdg637
关键词
angiotensin II; AT(2) receptor; cardiac hypertrophy; PLZF; transcription factor
资金
- NCI NIH HHS [P30 CA068485, CA-68485] Funding Source: Medline
- NHLBI NIH HHS [R01 HL058205, HL-58205, R37 HL058205] Funding Source: Medline
- NIDDK NIH HHS [DK-20593, P60 DK020593, P30 DK020593] Funding Source: Medline
We describe a novel signaling mechanism mediated by the G-protein-coupled receptor (GPCR) angiotensin II (Ang II) type 2 receptor (AT(2)). Yeast two-hybrid studies and affinity column binding assay show that the isolated AT(2) C-terminus binds to the transcription factor promyelocytic zinc finger protein (PLZF). Cellular studies employing confocal microscopy show that Ang II stimulation induces cytosolic PLZF to co-localize with AT(2) at the plasma membrane, then drives AT(2) and PLZF to internalize. PLZF slowly emerges in the nucleus whereas AT(2) accumulates in the perinuclear region. Nuclear PLZF binds to a consensus sequence of the phosphatidylinositol-3 kinase p85alpha subunit (p85alpha PI3K) gene. AT(2) enhances expression of p85alpha PI3K followed by enhanced p70(S6) kinase, essential to protein synthesis. An inactive mutant of PLZF abolishes this effect. PLZF is expressed robustly in the heart in contrast to many other tissues. This cardiac selective pathway involving AT(2), PLZF and p85alpha PI3K may explain the absence of a cardiac hypertrophic response in AT(2) gene-deleted mice.
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