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PMID: 7579691 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Integrin alpha 5 beta 1 expression negatively regulates cell growth: reversal by attachment to fibronectin.

Molecular biology of the cell ·Vol. 6 ·No. 6 ·1995-06-00 ·Pages 725-40

Varner JA, Emerson DA, Juliano RL

Abstract

Cells selected for overexpression of the integrin alpha 5 beta 1 show decreased proliferation and loss of the transformed phenotype. We provide evidence that de novo expression of the integrin alpha 5 beta 1 in HT29 colon carcinoma cells results in the growth arrest of these cells as characterized by reduced DNA synthesis and cellular proliferation in vitro. In fact, expression of integrin alpha 5 beta 1 on these cells induces the transcription of growth arrest specific gene 1 (gas-1), a gene product known to induce cellular quiescence, but blocks transcription of the immediate early genes c-fos, c-jun, and jun B. In vivo, the alpha 5 beta 1 transfectants display dramatically reduced tumorigenicity as well as a highly differentiated phenotype when compared with their pSVneo-transfected counterparts. Surprisingly, ligation of alpha 5 beta 1 on these cells by cell attachment to a fibronectin substrate not only reverses the growth inhibition and gas-1 gene induction but activates immediate early gene transcription. These findings demonstrate that integrin alpha 5 beta 1 expression in the absence of attachment to fibronectin activates a signaling pathway leading to decreased cellular proliferation and that ligation of this receptor with fibronectin reverses this signal, thereby contributing to the proliferation of transformed cells.

Related Genes
c-fos c-jun gas-1 jun B
MeSH Terms
Animals Base Sequence Cell Adhesion/drug effects Cell Count Cell Cycle/genetics Cell Cycle Proteins Cell Division/physiology Colonic Neoplasms Extracellular Matrix Proteins/metabolism Fibronectins/metabolism Flow Cytometry GPI-Linked Proteins Gene Expression Regulation Humans Membrane Proteins/biosynthesis Mice Mice, Nude Molecular Sequence Data Neoplasm Transplantation Protein Binding Proto-Oncogene Proteins/biosynthesis RNA, Messenger/analysis Receptors, Fibronectin/genetics,immunology,metabolism Signal Transduction Time Factors Transcriptional Activation Transfection Tumor Cells, Cultured/cytology
Chemicals
Cell Cycle Proteins Extracellular Matrix Proteins Fibronectins GAS1 protein, human GPI-Linked Proteins Gas1 protein, mouse Membrane Proteins Proto-Oncogene Proteins RNA, Messenger Receptors, Fibronectin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Varner J A
Department of Pharmacology, University of North Carolina, Chapel Hill 27599, USA.
Emerson D A
Juliano R L
References (75)
75 references, click to expand
  1. Inositol trisphosphate and calcium signalling.
    Nature. 1993 Jan 28;361(6410):315-25 PMID: 8381210
  2. Spreading of human endothelial cells on fibronectin or vitronectin triggers elevation of intracellular free calcium.
    J Cell Biol. 1993 Feb;120(4):1003-10 PMID: 7679387
  3. Cyclin-dependent regulation of G1 in mammalian fibroblasts.
    Science. 1993 Mar 26;259(5103):1908-12 PMID: 8384376
  4. Integrin beta 1- and beta 3-mediated endothelial cell migration is triggered through distinct signaling mechanisms.
    J Cell Biol. 1993 Apr;121(1):163-70 PMID: 7681432
  5. Negative regulation of G1 in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-beta.
    Science. 1993 Apr 23;260(5107):536-9 PMID: 8475385
  6. Adhesion to fibronectin stimulates inositol lipid synthesis and enhances PDGF-induced inositol lipid breakdown.
    J Cell Biol. 1993 May;121(3):673-8 PMID: 8387531
  7. A link between cyclin A expression and adhesion-dependent cell cycle progression.
    Science. 1993 Dec 3;262(5139):1572-5 PMID: 8248807
  8. The extracellular matrix as a cell survival factor.
    Mol Biol Cell. 1993 Sep;4(9):953-61 PMID: 8257797
  9. Osteoporosis induced in mice by overproduction of interleukin 4.
    Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11618-22 PMID: 8265598
  10. Structure, function, and chromosome mapping of the growth-suppressing human homologue of the murine gas1 gene.
    Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1848-52 PMID: 8127893
  11. Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen.
    Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8856-60 PMID: 7522323
  12. An interaction between alpha-actinin and the beta 1 integrin subunit in vitro.
    J Cell Biol. 1990 Aug;111(2):721-9 PMID: 2116421
  13. Activation of human CD4 T lymphocytes. Interaction of fibronectin with VLA-5 receptor on CD4 cells induces the AP-1 transcription factor.
    J Immunol. 1991 Jan 1;146(1):53-6 PMID: 1670606
  14. Oncogenes and signal transduction.
    Cell. 1991 Jan 25;64(2):281-302 PMID: 1846320
  15. Oncogenic conversion by regulatory changes in transcription factors.
    Cell. 1991 Jan 25;64(2):303-12 PMID: 1988149
  16. Growth factor-induced gene expression: the ups and downs of c-fos regulation.
    New Biol. 1990 Sep;2(9):751-8 PMID: 2279032
  17. Increased tumorigenicity of fibronectin receptor deficient Chinese hamster ovary cell variants.
    Cancer Res. 1991 Mar 15;51(6):1738-40 PMID: 1825619
  18. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc.
    Science. 1991 Mar 8;251(4998):1211-7 PMID: 2006410
  19. Fibronectin receptor overexpression and loss of transformed phenotype in a stable variant of the K562 cell line.
    Cell Regul. 1990 Aug;1(9):637-48 PMID: 2150333
  20. Hematopoietic development of embryonic stem cells in vitro: cytokine and receptor gene expression.
    Genes Dev. 1991 May;5(5):728-40 PMID: 1709130
  21. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF.
    Cell. 1991 May 17;65(4):663-75 PMID: 2032290
  22. Expression and role of integrins in adhesion of human colonic carcinoma cells to extracellular matrix components.
    Clin Exp Metastasis. 1991 Mar-Apr;9(2):163-78 PMID: 2032421
  23. Fibroblast surface antigen produced but not retained by virus-transformed human cells.
    J Exp Med. 1975 Aug 1;142(2):530-5 PMID: 167099
  24. Surface distribution of LETS protein in relation to the cytoskeleton of normal and transformed cells.
    J Cell Biol. 1977 Dec;75(3):743-68 PMID: 925079
  25. Similarities and differences between the fibronectins of normal and transformed hamster cells.
    J Biol Chem. 1981 Nov 25;256(22):11708-15 PMID: 6271758
  26. Dualistic nature of adhesive protein function: fibronectin and its biologically active peptide fragments can autoinhibit fibronectin function.
    J Cell Biol. 1984 Jul;99(1 Pt 1):29-36 PMID: 6736130
  27. Inositol trisphosphate and diacylglycerol as second messengers.
    Biochem J. 1984 Jun 1;220(2):345-60 PMID: 6146314
  28. Phosphorylation of the fibronectin receptor complex in cells transformed by oncogenes that encode tyrosine kinases.
    Proc Natl Acad Sci U S A. 1986 Sep;83(17):6470-4 PMID: 3018734
  29. The myc oncogene: its role in transformation and differentiation.
    Annu Rev Genet. 1986;20:361-84 PMID: 3028245
  30. Antisense RNA of proto-oncogene c-fos blocks renewed growth of quiescent 3T3 cells.
    Mol Cell Biol. 1987 Feb;7(2):639-49 PMID: 3547078
  31. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
    Anal Biochem. 1987 Apr;162(1):156-9 PMID: 2440339
  32. Absorptive and mucus-secreting subclones isolated from a multipotent intestinal cell line (HT-29) provide new models for cell polarity and terminal differentiation.
    J Cell Biol. 1987 Jul;105(1):345-57 PMID: 3611191
  33. A c-myc antisense oligodeoxynucleotide inhibits entry into S phase but not progress from G0 to G1.
    Nature. 1987 Jul 30-Aug 5;328(6129):445-9 PMID: 3302722
  34. Human osteosarcoma cells resistant to detachment by an Arg-Gly-Asp-containing peptide overproduce the fibronectin receptor.
    J Cell Biol. 1987 Sep;105(3):1175-82 PMID: 2443508
  35. Adherence induces selective mRNA expression of monocyte mediators and proto-oncogenes.
    J Immunol. 1988 Mar 1;140(5):1690-4 PMID: 3257980
  36. Microinjection of fos-specific antibodies blocks DNA synthesis in fibroblast cells.
    Mol Cell Biol. 1988 Apr;8(4):1670-6 PMID: 2454395
  37. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains.
    Science. 1988 Jul 1;241(4861):42-52 PMID: 3291115
  38. Transcriptional activation of c-jun during the G0/G1 transition in mouse fibroblasts.
    Nature. 1988 Aug 11;334(6182):535-7 PMID: 3136397
  39. Cell adhesion induces expression of growth-associated genes in suspension-arrested fibroblasts.
    Proc Natl Acad Sci U S A. 1988 Sep;85(18):6792-6 PMID: 3045824
  40. Growth factor receptor tyrosine kinases.
    Annu Rev Biochem. 1988;57:443-78 PMID: 3052279
  41. Induction of protooncogene c-jun by serum growth factors.
    Proc Natl Acad Sci U S A. 1988 Nov;85(22):8464-7 PMID: 3186736
  42. Receptor tyrosine kinase signaling required for integrin alpha v beta 5-directed cell motility but not adhesion on vitronectin.
    J Cell Biol. 1994 Nov;127(3):859-66 PMID: 7525598
  43. Integrin alpha v beta 3 differentially regulates adhesive and phagocytic functions of the fibronectin receptor alpha 5 beta 1.
    J Cell Biol. 1994 Nov;127(4):1129-37 PMID: 7525603
  44. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels.
    Cell. 1994 Dec 30;79(7):1157-64 PMID: 7528107
  45. Effect of cell spreading on cytoplasmic pH in normal and transformed fibroblasts.
    Proc Natl Acad Sci U S A. 1989 Jun;86(12):4525-9 PMID: 2734302
  46. Control of the higher eukaryote cell cycle by p34cdc2 homologues.
    Biochim Biophys Acta. 1989 Jul 28;989(1):85-95 PMID: 2546600
  47. Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression.
    J Cell Biol. 1989 Aug;109(2):877-89 PMID: 2547805
  48. The protein kinase C family: heterogeneity and its implications.
    Annu Rev Biochem. 1989;58:31-44 PMID: 2549852
  49. Serum-inducible genes.
    Adv Cancer Res. 1989;53:1-32 PMID: 2678945
  50. pH regulation in spread cells and round cells.
    J Biol Chem. 1990 Jan 25;265(3):1327-32 PMID: 2153127
  51. The osteoblast-like differentiated phenotype of a variant of MG-63 osteosarcoma cell line correlated with altered adhesive properties.
    Connect Tissue Res. 1989;20(1-4):49-61 PMID: 2533054
  52. Elevated levels of the alpha 5 beta 1 fibronectin receptor suppress the transformed phenotype of Chinese hamster ovary cells.
    Cell. 1990 Mar 9;60(5):849-59 PMID: 2155708
  53. Universal control mechanism regulating onset of M-phase.
    Nature. 1990 Apr 5;344(6266):503-8 PMID: 2138713
  54. Signal transduction by receptors with tyrosine kinase activity.
    Cell. 1990 Apr 20;61(2):203-12 PMID: 2158859
  55. Monocyte adherence results in selective induction of novel genes sharing homology with mediators of inflammation and tissue repair.
    J Immunol. 1990 Jun 1;144(11):4434-41 PMID: 2341726
  56. Changes in integrin receptors on oncogenically transformed cells.
    Cell. 1989 Jan 27;56(2):281-90 PMID: 2521461
  57. Growth factor production by human colon carcinoma cell lines.
    Cancer Res. 1989 Jun 1;49(11):2898-904 PMID: 2541895
  58. Characterization of an immediate-early gene induced in adherent monocytes that encodes I kappa B-like activity.
    Cell. 1991 Jun 28;65(7):1281-9 PMID: 1829648
  59. Microcarcinoma in the prostate: its association with duct-acinar dysplasia.
    Hum Pathol. 1991 Jul;22(7):644-52 PMID: 1712748
  60. The jun and fos protein families are both required for cell cycle progression in fibroblasts.
    Mol Cell Biol. 1991 Sep;11(9):4466-72 PMID: 1908553
  61. Insoluble fibronectin activates the Na/H antiporter by clustering and immobilizing integrin alpha 5 beta 1, independent of cell shape.
    Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7849-53 PMID: 1652767
  62. Primary response genes induced by growth factors and tumor promoters.
    Annu Rev Biochem. 1991;60:281-319 PMID: 1883198
  63. Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of beta 1 integrins.
    Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8392-6 PMID: 1717976
  64. Dihydrofolate reductase gene amplification-associated shift of differentiation in methotrexate-adapted HT-29 cells.
    J Cell Biol. 1991 Dec;115(5):1409-18 PMID: 1955481
  65. Cell cycle-regulated and proliferation stimulus-responsive genes.
    Crit Rev Eukaryot Gene Expr. 1991;1(4):247-300 PMID: 1802111
  66. Integrins: versatility, modulation, and signaling in cell adhesion.
    Cell. 1992 Apr 3;69(1):11-25 PMID: 1555235
  67. Induction of apoptosis in fibroblasts by c-myc protein.
    Cell. 1992 Apr 3;69(1):119-28 PMID: 1555236
  68. Inhibition of c-jun causes reversible proliferative arrest and withdrawal from the cell cycle.
    Blood. 1992 Apr 15;79(8):2107-15 PMID: 1562737
  69. Adhesion is required for protein kinase C-dependent activation of the Na+/H+ antiporter by platelet-derived growth factor.
    Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6138-41 PMID: 1378621
  70. Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation.
    Nature. 1992 Aug 20;358(6388):690-2 PMID: 1379699
  71. The growth arrest-specific gene, gas1, is involved in growth suppression.
    Cell. 1992 Aug 21;70(4):595-607 PMID: 1505026
  72. An altered repertoire of fos/jun (AP-1) at the onset of replicative senescence.
    Exp Cell Res. 1992 Sep;202(1):161-6 PMID: 1511730
  73. Signal transduction by the platelet integrin alpha IIb beta 3: induction of calcium oscillations required for protein-tyrosine phosphorylation and ligand-induced spreading of stably transfected cells.
    Mol Biol Cell. 1992 Sep;3(9):989-98 PMID: 1421580
  74. Fibronectin receptor modulates cyclin-dependent kinase activity.
    J Biol Chem. 1992 Dec 25;267(36):25744-7 PMID: 1464591
  75. Signal transduction from the extracellular matrix.
    J Cell Biol. 1993 Feb;120(3):577-85 PMID: 8381117
Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.6.6.725
Published
1995-06-00
Pages
725-40
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC301232
Subset
IM
Grants
PHS HHS · 26165 · United States
NIDDK NIH HHS · DK-34987 · United States
External Links
PubMed source DOI: 10.1091/mbc.6.6.725 PMC Full Text View journal details
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