HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yan, Z. Articles by Friedman, E. Search for Related Content PubMed PubMed Citation Articles by Yan, Z. Articles by Friedman, E. Social Bookmarking                      What's this?

Volume 272, Number 49, Issue of December 5, 1997 pp. 30928-30936
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Oncogenic Ki-ras but Not Oncogenic Ha-ras Blocks Integrin 1-Chain Maturation in Colon Epithelial Cells

(Received for publication, April 3, 1997, and in revised form, September 12, 1997)

Zhongfa Yan , Ming-xing Chen , Manuel Perucho and Eileen Friedman

From the State University of New York Health Science Center, Department of Pathology, Syracuse, New York 13210 and the  Burnham Institute, La Jolla, California 92037

Human colorectal tumors commonly contain mutations in Ki-ras but rarely, if ever, in Ha-ras. The selectivity for Ki-ras mutations in this tumor was explored using the HD6-4 colon epithelial cell line which contains no ras mutations. After adhesion to an extracellular matrix, HD6-4 cells polarize into columnar goblet cells with distinct apical and basal regions. Stable HD6-4 transfectants were made with mini-gene constructs of the oncogenic cellular Ki-ras4B^G12V gene, the oncogenic Ha-ras^G12V gene, or mini-gene constructs of wild-type Ki-ras4B as a control. Ki-ras mutations, but not Ha-ras mutations, disrupted colon epithelial cell apicobasal polarity and adhesion to collagen I and laminin. Three Ha-ras transfectants and three Ki-ras transfectants exhibited Ras proteins expressing the Val-12 mutation by Western blotting with pan-ras^G12V antibody. Only wild-type Ki-ras transfectant cells and oncogenic Ha-ras transfectant cells synthesized the mature, fully glycosylated forms of 1 integrin. Instead of the mature integrin 1-chain, a faster migrating 1-chain intermediate was detected on the cell surface and in the cytoplasm of the oncogenic Ki-ras transfectants. Expression of the oncogenic Ki-ras gene caused the altered 1 integrin maturation because phosphorothiolated antisense oligonucleotides to Ki-ras reduced expression of both the mutant Ki-Ras protein and the aberrant integrin 1-chain and increased expression of the mature integrin 1-chain. Altered glycosylation generated the new 1 integrin form since integrin core 1-chain proteins of the same molecular weight were yielded in Ki-ras, Ha-ras, and control transfectants after removal of sugar residues with endoglycosidase F or following tunicamycin treatment to inhibit glycosylation. The selective effect of oncogenic Ki-ras on 1 integrin glycosylation was not due to selective activation of mitogen-activated protein kinases because both mutated Ki- and Ha-ras genes activated this pathway and increased cell proliferation. Since blocking the glycosylation of integrin 1-chain inhibited the adherence, polarization, and subsequent differentiation of colon epithelial cells, the selective effects of the oncogenic cellular Ki-ras gene on integrin 1-chain glycosylation may account, at least in part, for the selection of Ki-ras mutations in human colon tumors.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Vijayakumar, H. Erdjument-Bromage, P. Tempst, and Q. Al-Awqati Role of Integrins in the Assembly and Function of Hensin in Intercalated Cells J. Am. Soc. Nephrol., June 1, 2008; 19(6): 1079 - 1091. [Abstract] [Full Text] [PDF]

				X. Shen, M.-S. Hong, J. Moss, and M. Vaughan BIG1, a brefeldin A-inhibited guanine nucleotide-exchange protein, is required for correct glycosylation and function of integrin beta1 PNAS, January 23, 2007; 104(4): 1230 - 1235. [Abstract] [Full Text] [PDF]

				S. Svegliati, R. Cancello, P. Sambo, M. Luchetti, P. Paroncini, G. Orlandini, G. Discepoli, R. Paterno, M. Santillo, C. Cuozzo, et al. Platelet-derived Growth Factor and Reactive Oxygen Species (ROS) Regulate Ras Protein Levels in Primary Human Fibroblasts via ERK1/2: AMPLIFICATION OF ROS AND Ras IN SYSTEMIC SCLEROSIS FIBROBLASTS J. Biol. Chem., October 28, 2005; 280(43): 36474 - 36482. [Abstract] [Full Text] [PDF]

				J. B. Fleming, G.-L. Shen, S. E. Holloway, M. Davis, and R. A. Brekken Molecular Consequences of Silencing Mutant K-ras in Pancreatic Cancer Cells: Justification for K-ras-Directed Therapy Mol. Cancer Res., July 1, 2005; 3(7): 413 - 423. [Abstract] [Full Text] [PDF]

				A. C. Semel, E. C. Seales, A. Singhal, E. A. Eklund, K. J. Colley, and S. L. Bellis Hyposialylation of Integrins Stimulates the Activity of Myeloid Fibronectin Receptors J. Biol. Chem., August 30, 2002; 277(36): 32830 - 32836. [Abstract] [Full Text] [PDF]

				P. J. Ross, M. George, D. Cunningham, F. DiStefano, H. J. N. Andreyev, P. Workman, and P. A. Clarke Inhibition of Kirsten-ras Expression in Human Colorectal Cancer Using Rationally Selected Kirsten-ras Antisense Oligonucleotides Mol. Cancer Ther., November 1, 2001; 1(1): 29 - 41. [Abstract] [Full Text] [PDF]

				K. Lee, X. Deng, and E. Friedman Mirk Protein Kinase Is a Mitogen-activated Protein Kinase Substrate That Mediates Survival of Colon Cancer Cells Cancer Res., July 1, 2000; 60(13): 3631 - 3637. [Abstract] [Full Text]

				L. A. Quilliam, A. F. Castro, K. S. Rogers-Graham, C. B. Martin, C. J. Der, and C. Bi M-Ras/R-Ras3, a Transforming Ras Protein Regulated by Sos1, GRF1, and p120 Ras GTPase-activating Protein, Interacts with the Putative Ras Effector AF6 J. Biol. Chem., August 20, 1999; 274(34): 23850 - 23857. [Abstract] [Full Text] [PDF]

				C. C. SHARPE, M. E. C. DOCKRELL, R. SCOTT, M. I. NOOR, L. M. COWSERT, B. P. MONIA, and B. M. HENDRY Evidence of a Role for Ki-RAS in the Stimulated Proliferation of Renal Fibroblasts J. Am. Soc. Nephrol., June 1, 1999; 10(6): 1186 - 1192. [Abstract] [Full Text]

				X. Deng, S. Bellis, Z. Yan, and E. Friedman Differential Responsiveness to Autocrine and Exogenous Transforming Growth Factor (TGF) {beta}1 in Cells with Nonfunctional TGF-{beta} Receptor Type III Cell Growth Differ., January 1, 1999; 10(1): 11 - 18. [Abstract] [Full Text]

				Z. Yan, X. Deng, and E. Friedman Oncogenic Ki-ras Confers a More Aggressive Colon Cancer Phenotype through Modification of Transforming Growth Factor-beta Receptor III J. Biol. Chem., January 5, 2001; 276(2): 1555 - 1563. [Abstract] [Full Text] [PDF]

				G. Cuda, R. Paterno, R. Ceravolo, M. Candigliota, N. Perrotti, F. Perticone, M. C. Faniello, F. Schepis, A. Ruocco, E. Mele, et al. Protection of Human Endothelial Cells From Oxidative Stress: Role of Ras-ERK1/2 Signaling Circulation, February 26, 2002; 105(8): 968 - 974. [Abstract] [Full Text] [PDF]