Abstract

The long-term goal of our laboratory is to define the molecular mediators and signaling intermediates of human melanocyte (HM) dendricity & melanosome (MS) transfer. Prostaglandins (PG) are lipid signaling molecules released by keratinocytes in response to UVR. Our global hypothesis is that PG stimulate HM pigmentation through the action of specific PG receptors that are increased by UVR. We propose that these receptors (EP1, EP3 and FP) activate Rac/Cdc42 and or inhibit Rho, which we have shown in the first funding period mediate HM dendricity and MS transfer. Since submission of this revised proposal we have defined the profile of PGE2 & PGF2_ receptors in HM, have identified which PG receptors that mediate HM dendricity & have shown a particularly important role for the PGF2_ receptor (FP) in HM dendricity and pigmentation. New data indicate that secretory phospholipase (sPLA2) -X modulates HM dendricity and pigmentation through the release of the lysophospholipid (LPL) lysophosphatidylcholine. The first two aims will define signaling intermediates that mediate PG-dependent dendricity, and MS transfer and will analyze PG receptor regulation by UVR and paracrine/autocrine factors. Receptor expression in HM in skin in vivo and regulation by UVR will be examined & identification of PG produced by HM will be analyzed. Based on new preliminary data, we hypothesize that effects of sPLA2(s) on HM are not mediated primarily by arachidonic acid-dependent PG production but rather through receptor or non-receptor dependent action of LPL on HM. In the third aim we will define effects of sPLA2 & LPL & fatty acids resulting from secretory phospholipase activity on HM dendricity and MS transfer, and will identify potential receptors that mediate this effect. Finally, we will examine the function of cytosolic PLA2 (cPLA2) on HM and its potential regulation by UVR. We hypothesize that PG and phospholipases stimulate HM dendricity, MS transfer & pigmentation through different mechanisms that act synergistically to modulate cutaneous pigmentation following UVR.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045427-07
Application #
7126930
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
1999-09-27
Project End
2010-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
7
Fiscal Year
2006
Total Cost
$335,135
Indirect Cost

  Institution

Name
University of Rochester
Department
Dermatology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627

  Publications

McClelland, Lindy; Chen, Yulin; Soong, Joanne et al. (2011) Plexin B1 inhibits integrin-dependent pp125FAK and Rho activity in melanoma. Pigment Cell Melanoma Res 24:165-74
Starner, Renny J; McClelland, Lindy; Abdel-Malek, Zalfa et al. (2010) PGE(2) is a UVR-inducible autocrine factor for human melanocytes that stimulates tyrosinase activation. Exp Dermatol 19:682-4
Stevens, Laurel; McClelland, Lindy; Fricke, Alex et al. (2010) Plexin B1 suppresses c-Met in melanoma: a role for plexin B1 as a tumor-suppressor protein through regulation of c-Met. J Invest Dermatol 130:1636-45
Fricke, Alex; McClelland, Lindy; Scott, Glynis (2010) The PGF(2alpha) receptor FP is lost in nevi and melanoma. Pigment Cell Melanoma Res 23:141-3
Scott, Glynis A; McClelland, Lindy A; Fricke, Alex F (2008) Semaphorin 7a promotes spreading and dendricity in human melanocytes through beta1-integrins. J Invest Dermatol 128:151-61
Scott, Glynis A; Arioka, Manubu; Jacobs, Stacey E (2007) Lysophosphatidylcholine mediates melanocyte dendricity through PKCzeta activation. J Invest Dermatol 127:668-75
Scott, Glynis; Fricke, Alex; Fender, Anne et al. (2007) Prostaglandin E2 regulates melanocyte dendrite formation through activation of PKCzeta. Exp Cell Res 313:3840-50
Scott, Glynis A; Jacobs, Stacey E; Pentland, Alice P (2006) sPLA2-X stimulates cutaneous melanocyte dendricity and pigmentation through a lysophosphatidylcholine-dependent mechanism. J Invest Dermatol 126:855-61
Scott, Glynis; Jacobs, Stacey; Leopardi, Sonya et al. (2005) Effects of PGF2alpha on human melanocytes and regulation of the FP receptor by ultraviolet radiation. Exp Cell Res 304:407-16
Scott, Glynis; Leopardi, Sonya (2003) The cAMP signaling pathway has opposing effects on Rac and Rho in B16F10 cells: implications for dendrite formation in melanocytic cells. Pigment Cell Res 16:139-48

Showing the most recent 10 out of 13 publications