Regulation of epithelial differentiation and proliferation by the stroma: a role for the retinoblastoma protein.
Signaling between the epithelium and stromal cells is crucial for growth, differentiation, and repair of the epithelium. Although the retinoblastoma protein (Rb) is known to regulate the growth of keratinocytes in a cell-autonomous manner, here we describe a function of Rb in the stromal compartment. We find that Rb depletion in fibroblasts leads to inhibition of differentiation and enhanced proliferation of the epithelium. Analysis of conditioned medium identified that keratinocyte growth factor (KGF) levels were elevated following Rb depletion. These findings were also observed with organotypic co-cultures. Treatment of keratinocytes with KGF inhibited differentiation and enhanced keratinocyte proliferation, whereas reduction of KGF levels in Rb-depleted fibroblasts was able to restore expression of differentiation markers. Our findings suggest a crucial role for dermal fibroblasts in regulating the differentiation and proliferation of keratinocytes, and we demonstrate a role for stromal Rb in this cross-talk.
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
Adam
A
Pickard
Ann-Christin
AC
Cichon
Craig
C
Menges
Daksha
D
Patel
Dennis J
DJ
McCance
D002454:Cell Differentiation / Q000502:physiology; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000254:growth & development / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D052816:Foreskin / Q000166:cytology; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D008297:Male; D009055:Mouth / Q000166:cytology; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism
D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D016160:Retinoblastoma Protein