Overexpression of the oncofetal Fn variant containing the EDA splice-in segment in the dermal-epidermal junction of psoriatic uninvolved skin.
The extracellular matrix protein, Fn, has critical functions in cell attachment, migration, differentiation, and proliferation. We have previously shown that fibronectin (Fn) is abnormally expressed and potentiates entry into the cell cycle of basal keratinocytes in uninvolved psoriatic skin, in combination with T cell lymphokines. It is not known what type of Fn is present in psoriatic skin, however, and how this Fn may regulate signaling. Embryonic forms of cellular Fn containing extra domains, designated EDA and EDB, are generated by alternative splicing and are seen in proliferating, developing tissue and in wound healing. Because the EDA segment enhances the integrin binding sequence Arg, Gly, Asp (RGD), which, when present, has been shown to be critical in integrin-extracellular matrix signaling, we were particularly interested in determining whether or not EDA-containing Fn (EDA+Fn) represented the aberrantly expressed Fn in psoriasis. Increased EDA+ Fn protein was demonstrated by immunostaining at the dermal-epidermal junction in clinically uninvolved skin from six of six patients with psoriasis, but not in skin from control subjects. Using reverse transcription polymerase chain reaction an increased ratio of EDA+ Fn versus EDA- Fn mRNA was present in epidermal samples from psoriatic but not control individuals. Interestingly, the EDA+Fn in the psoriatic epidermis had the IIICS region spliced out (EDA+, FDB-, IIICS-, III9+), which was shared with normal epidermis (EDA-, EDB-, IIICS-, III9+). These results suggest a selective predominance of the EDA+ Fn isoform at the dermal-epidermal junction of psoriatic skin. The consistent aberrant localization of EDA+ Fn at the dermal-epidermal junction in uninvolved skin of psoriatics may confer the hyperresponsiveness of psoriatic uninvolved basal keratinocytes for rapid cellular proliferation in response to T cell signals. Key words: immunohistochemistry/integrin/keratinocyte/RT-PCR.
Ting
K M
KM
Departments of Dermatology and Microbiology and Molecular Biology, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio 44106-5028, USA.
Rothaupt
D
D
McCormick
T S
TS
Hammerberg
C
C
Chen
G
G
Gilliam
A C
AC
Stevens
S
S
Culp
L
L
Cooper
K D
KD
D003876:Dermatitis, Atopic / Q000378:metabolism; D053331:Ectodysplasins; D004817:Epidermis / Q000378:metabolism*; D005353:Fibronectins / Q000737:chemistry / Q000235:genetics*; D015870:Gene Expression; D014644:Genetic Variation; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis; D017434:Protein Structure, Tertiary / Q000502:physiology; D011565:Psoriasis / Q000235:genetics*; D012326:RNA Splicing; D012867:Skin / Q000737:chemistry*
C506018:EDA protein, human; D053331:Ectodysplasins; D005353:Fibronectins; D008565:Membrane Proteins; C121542:oncofetal fibronectin