Transforming growth factor beta 1 suppresses transformation in hepatocytes by regulating alpha 1 beta 1 integrin expression.
We previously reported that (a) treatment of the ras-transformed hepatocyte cell line NR4 with transforming growth factor (TGF) beta 1 suppresses many characteristics associated with the transformed phenotype including altered morphology, actin cytoskeleton reorganization, and anchorage-independent growth such that the cells more closely resemble the immortalized CWSV1 parent cell line; (b) transformed NR4 cells expressed significantly less alpha 1 integrin RNA than the immortalized CWSV1 cells; and (c) TGF-beta 1 treatment of NR4 cells stimulated the expression of alpha 1 and beta 1 integrin RNAs. In this report, the role of the alpha 1 beta 1 integrin in TGF-beta 1-mediated suppression of the ras-transformed phenotype was investigated. We determined that (a) the cell surface integrin that increased in response to TGF-beta 1 treatment of NR4 cells was alpha 1 integrin; (b) TGF-beta 1 altered the ability of NR4 cells to attach to collagen and laminin, the extracellular matrix components that interact with the alpha 1 beta 1 integrin receptor; (c) TGF-beta 1 treatment resulted in relocalization of the alpha 1 integrin on the NR4 cell surface; and (d) TGF-beta 1-mediated inhibition of anchorage-independent growth was blocked by the presence of alpha 1 integrin antibody. A cell line that overexpresses alpha 1 integrin was derived from NR4 cells; characterization of these cells indicated that they continued to express H-ras RNA but were less transformed than the parent NR4 cells. Specifically, they had an altered morphology, an organized actin cytoskeleton, and reduced ability to demonstrate anchorage-independent growth.(ABSTRACT TRUNCATED AT 250 WORDS)
Serra
R
R
Department of Microbiology and Immunology, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey 17033.
Carbonetto
S
S
Lord
M
M
Isom
H C
HC
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D011905:Genes, ras / Q000502:physiology; D039222:Integrin alpha1beta1; D016023:Integrins / Q000096:biosynthesis* / Q000235:genetics; D007797:Laminin / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D039222:Integrin alpha1beta1; D016023:Integrins; D007797:Laminin; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003094:Collagen