Abstract
Stromelysin is a metalloproteinase with the widest substrate specificity that plays a critical role in the induction of the metastatic phenotype in cancer cells. The mechanisms whereby growth factors and oncogenes control stromelysin expression are beginning to be characterized. We have recently demonstrated that protein kinase C isotypes down-regulatable by chronic exposure to phorbol esters are not involved in stromelysin gene expression in response to platelet-derived growth factor, ras oncogene, and phosphatidylcholine-hydrolyzing phospholipase C. We also identified a region in the stromelysin promoter, distinct from the 12-O-tetradecanoylphorbol-13-acetate-responsive element, responsible for the promoter activity in response to these stimulants. In this paper, we further characterize that promoter fragment and demonstrate that the region encompassing nucleotides -1218 to -1202, including the palindromic sequence ACTAGT, is necessary and sufficient for the control of stromelysin gene expression. The involvement of zeta-protein kinase C but not of c-raf in the stimulation of stromelysin promoter activity in response to platelet-derived growth factor is also demonstrated here. All these data suggest the existence of a bifurcation downstream of ras in the signaling mechanisms leading to stromelysin expression and DNA synthesis.
Highlights
Stromelysin is a metalloproteinase with the widest their levels correlate with the metastatic staotuf s everal cansubstrate specificity that plays acritical role in the in- cer cell lines [7,8,9]
We have recently demonstrated that protein nectin, laminin, collagen IV, and diverse proteoglycans[13]. kinase C isotypesdown-regulatableby chronic exposure The expression of stromelysin or its rat homolog, transin, is tpsetootxhrrpopo,rsmhrepousehrssloboyiolsnoiniplcnoeaingsspteerernoreCemss.,paoW oartnneeersdn,edaoilpttssohtoiinopnisvlcdpaotehtlfvenareltotediimtfd-iieydntdlehcrsehativorr1oeel2igdmn-i0geoe--rnlthoyeywstidrntiarnhodgfleteyahcnzcaeei-n- g(msi1nu7etbe1tjhr,elacaestnuodktnoiedno(u-n1lca4pol,rg(e1eg1n4u5e,l)saEot()ir1o,8ntpr).hEa,ownnrshzbfyeoormlremeeasssitnyegnirtsthgi(ers1os6swisu,it1phs7pf1ar,cegtsorsroe+iwdndtbhuy(cf1aed9cde)t.oxbraIys-t noylphorbol-13-acetate-responsiveelement, responsible would be of great interest to unveil the mechanisms whereby for the promoter activity in response to these stimu- growth factors and oncogenes control the expression of stromelants
Moter fragment and demonstrate tthhaetregion encom- Recently, we and others haviedentified a novel required step passing nucleotides -1218 to -1202i,ncluding the in these cascades; activation by growth factors and oncogene palindromic sequence ACTAGT, is necessary and suffi- products of a phospholipase C specific for phosphatidylcholine cient for the control of stromelysin gene expressionT.he (PC-PLC) hasbeen shown to be both necessary and sufficient involvement of g-proteinkinase C but not of c-ruf tihne for mitogenic activation [20,21,22,23,24,25,26,27,28]
Summary
Regulation of genetranscriptionis associated with cell PMA-sensitive PKCs to an extent similator that found in cells growth and tumor transformation [1].At the first level, the with normal PKC levels [23, 29]. 2 not involve the 12-0-tetradecanoylphorbol-13-acetate-responand 3) play critical roles as tertiary messengers in the tran- sive element existing in the stromelypsroinmoter but utilizesa scriptional regulationof a number of second-phase genes; these potentially novel element located in the region encompassing are crucial to the maintenanceof the normalcell phenotype, as nucleotides -1240 to -1145 of that promoter [29]. These results well a s t o the degree of tumor invasiveness and metastatic would be consistent with our recent data demonstrating the potential [4,5,6]. IndSutcrotimoPneKlyCsinand more important, we demonstrate here thienvolvement of
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