DIFFERENT STABILITY OF AP1 PROTEINS IN HUMAN KERATINOCYTE AND FIBROBLAST CELLS - POSSIBLE ROLE IN THE CELL-TYPE-SPECIFIC EXPRESSION OF HUMAN PAPILLOMAVIRUS TYPE-18 GENES
Ea. Offord et al., DIFFERENT STABILITY OF AP1 PROTEINS IN HUMAN KERATINOCYTE AND FIBROBLAST CELLS - POSSIBLE ROLE IN THE CELL-TYPE-SPECIFIC EXPRESSION OF HUMAN PAPILLOMAVIRUS TYPE-18 GENES, Carcinogenesis, 14(12), 1993, pp. 2447-2455
Human papillomaviruses (HPV) replicate in keratinocyte but not fibrobl
ast cells. several factors, including AP1 (Jun/Fos), contribute to the
cell-type specific transcription of HPV genes. The binding of AP1 ups
tream of the HPV type 18 early gene E6 is essential for transcription
of the early genes. Here we show that AP1 levels are low in early pass
age human fibroblast extracts. In contrast, human keratinocyte extract
s contain high levels of AP1. In agreement with this, in vivo an AP1-d
ependent promoter is more active in keratinocytes than in fibroblasts.
Pulse chase experiments indicated that Jun and Fos are relatively sta
ble in human keratinocyte cells after serum induction, whereas in earl
y passage human fibroblasts they are rapidly broken down. Nuclear extr
acts of these fibroblasts contain a cysteine proteinase which can degr
ade AP1. Furthermore, the activity of a cathepsin B-like cysteine prot
einase is elevated in these human fibroblast extracts relative to othe
r cell types. Interestingly, after several passages in culture the fib
roblasts lose this proteinase activity and the amount of AP1 increases
. Taken together, these results suggest that the quantitative differen
ce in API proteins between human keratinocytes and fibroblasts is due
to a difference in protein stability. The cathepsin B-like cysteine pr
oteinase is a candidate for a role in the unusually rapid breakdown of
AP1 in early passage human fibroblast cells. Low levels of AP1 in the
fibroblasts correlate with the low activity of AP1-dependent promoter
s, like that of HPV-18, in these cells.