Loss of metal transcription factor-1 suppresses tumor growth through enhanced matrix deposition.
Metal transcription factor-1 (MTF-1) is a ubiquitous transcriptional regulator and chromatin insulator with roles in cellular stress responses and embryonic development. The studies described herein establish for the first time the involvement of MTF-1 in tumor development. Genetically manipulated ras-transformed mouse embryonic fibroblasts (MEFs), wild-type (MTF-1+/+), or nullizygous for MTF-1 (MTF-1-/-) were used to develop fibrosarcoma tumors. Loss of MTF-1 resulted in delayed tumor growth associated with increased matrix collagen deposition and reductions in vasculature density. Molecular consequences of MTF-1 loss include increased expression and activation of the transforming growth factor-beta1 (TGF-beta1) and tissue transglutaminase (tTG), two proteins with documented roles in the production and stabilization of extracellular matrix (ECM). Our findings support the hypothesis that MTF-1 enhances the ability of the developing tumor mass to evade fibrosis and scarring of the tumor, a critical step in tumor cell proliferation.
Biosciences Division, SRI International, Menlo Park, CA 94025, USA.
Zishan A
ZA
Haroon
Khalid
K
Amin
Peter
P
Lichtlen
Barbara
B
Sato
Nhung T
NT
Huynh
Zhaohui
Z
Wang
Walter
W
Schaffner
Brian J
BJ
Murphy
D000818:Animals; D002455:Cell Division / Q000235:genetics; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins; D018450:Disease Progression; D004790:Enzyme Induction; D005109:Extracellular Matrix / Q000378:metabolism; D005341:Fibrinolysin / Q000032:analysis; D005347:Fibroblasts / Q000473:pathology / Q000637:transplantation; D005354:Fibrosarcoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D011905:Genes, ras; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1; D011503:Transglutaminases / Q000096:biosynthesis / Q000235:genetics; D000097809:Transcription Factor MTF-1
D004268:DNA-Binding Proteins; D005341:Fibrinolysin; D019204:GTP-Binding Proteins; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D011503:Transglutaminases; D000097809:Transcription Factor MTF-1; C508961:Tgfb1 protein, mouse