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Vitamin D enhances mitogenesis mediated by keratinocyte growth factor receptor in keratinocytes
Author(s) -
Gamady Anat,
Koren Ruth,
Ron Dina,
Liberman Uri A.,
Ravid Amiram
Publication year - 2003
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.10508
Subject(s) - keratinocyte growth factor , autocrine signalling , paracrine signalling , keratinocyte , hacat , endocrinology , fibroblast growth factor , medicine , tyrosine kinase , mapk/erk pathway , epidermal growth factor , biology , microbiology and biotechnology , receptor , kinase , chemistry , signal transduction , cell culture , genetics
The hormonally active vitamin D metabolite, 1,25‐dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), and keratinocyte growth factor (KGF) belong to the network of autocrine and paracrine mediators in the skin. Both were shown to modulate keratinocyte proliferation, to reverse epidermal atrophy, to increase wound healing, and to reduce chemotherapy‐induced alopecia. The overlap between their activities may suggest that vitamin D exerts some of its actions by modulation of KGF activities in the skin. This notion was examined by using HaCaT keratinocytes cultured in serum‐free medium in the absence of exogenous growth factors and in the presence of the EGF receptor tyrosine kinase inhibitor AG 1478 that blocks their autonomous proliferation. These cells could be stimulated to proliferate by different fibroblast growth factors (FGFs). The relative mitogenic efficacy of basic FGF, acidic FGF, or KGF was in correlation with their affinities for the KGF receptor (KGFR). Forty‐eight hour co‐treatment with 1,25(OH) 2 D 3 enhanced KGFR‐mediated cell proliferation in a dose dependent manner. Both ERK1/2 and c‐Jun N‐terminal kinase (JNK) were activated by the FGFs. Treatment with 1,25(OH) 2 D 3 increased the activation of ERK but reduced the activation of JNK. Treatment with 1,25(OH) 2 D 3 increased the levels of KGFR in the presence but not in the absence of KGF, probably due to inhibition of ligand‐induced receptor degradation. Inhibition of protein kinase C with bisindolylmaleimide did not interfere with the effect of 1,25(OH) 2 D 3 on KGFR‐mediated ERK activation. Our results support the notion that the paracrine KGF–KGFR system in the skin can act in concert with the autocrine vitamin D system in keratinocytes to promote keratinocyte proliferation and survival under situations of stress and injury. J. Cell. Biochem. 89: 440–449, 2003. © 2003 Wiley‐Liss, Inc.

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