Chronic wound fluid suppresses proliferation of dermal fibroblasts through a Ras-mediated signaling pathway.
Wound fluid collected from chronic venous leg ulcers (chronic wound fluid (CWF)) has been shown to inhibit the growth of dermal fibroblasts by interfering with cell-cycle progression from G1 into S phase. Specifically, CWF was shown to downregulate the levels of hyperphosphorylated retinoblastoma tumor-suppressor gene (Rb) and cyclin D1, known to be critical for entering the S phase of the cell cycle. To further elucidate the effects of CWF, a Ras-mediated signaling pathway involving the mitogen-activated protein kinase kinase (MEK), known to modulate the expression of these cell-cycle-regulatory proteins, was examined. Transient transfection of dermal fibroblasts with constitutively active Ras abrogated the growth suppressive effects of CWF on hyperphosphorylated Rb (ppRb) and cyclin D1. In contrast, an MEK inhibitor PD 98059 mimicked the effects of CWF on these cell-cycle-regulatory proteins. Concurrent treatment with PD 98059 and CWF produced additive effects. Taken together, these results suggest that CWF inhibits the growth of dermal fibroblasts at least in part by decreasing the level of active Ras, resulting in decreased levels of ppRb and cyclin D1. Therefore, a Ras-dependent signaling pathway may mediate the growth inhibitory effect of CWF, and reconstitution of Ras activity may overcome this growth inhibitory effect.
Seah
Ching Ching
CC
Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, Massachusetts 02118, USA.
Phillips
Tania J
TJ
Howard
Courtney E
CE
Panova
Izabela P
IP
Hayes
Christine M
CM
Asandra
Amy S
AS
Park
Hee-Young
HY
D017209:Apoptosis / Q000502:physiology; D001826:Body Fluids / Q000378:metabolism*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000494:pharmacology; D020405:Dermis / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D016192:Resting Phase, Cell Cycle / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014647:Varicose Ulcer / Q000378:metabolism* / Q000473:pathology; D014945:Wound Healing / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism*
D016160:Retinoblastoma Protein; D019938:Cyclin D1; D018631:ras Proteins