Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 277, Issue 41, Pages 38965-38971Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M203736200
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Funding
- NIAID NIH HHS [AI35884, AI20015] Funding Source: Medline
- NIGMS NIH HHS [GM42259] Funding Source: Medline
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1,25(OH)(2)D-3 antiproliferative properties are widely known. However, the molecular bases of these properties are only partially elucidated. Since 1,25(OH)(2)D-3 effectively arrests growth in many tumors and hyperplastic tissues whose growth is driven by co-expression of EGFR and its ligand TGF-alpha, it was hypothesized that 1,25(OH)(2)D-3 could affect the TGF-alpha/EGFR-autocrine growth loop. This study examined 1,25(OH)(2)D-3 regulation of EGFR-growth signals, using human epidermoid A431 cells, in which the overexpression of EGFR and TGF-a constitute the major autocrine mitogenic signal. 1,25(OH)(2)D-3 inhibited autocrine and EGF-induced A431 cell proliferation. Furthermore, 1,25(OH)(2)D-3 changed the cellular localization of both TGF-alpha and EGFR and inhibited ligand-dependent phosphorylation of EGFR and ERK1/2. In addition, 1,25(OH)(2)D-3 impaired autocrine and EGF-induced nuclear translocation of activated EGFR and, consequently, its binding to AT-rich DNA sequences and transcriptional activation of the cyclin D1 promoter. These results demonstrate that 1,25(OH)(2)D-3 alters EGFR membrane trafficking and down-regulates EGFR growth signaling.
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