The DCC Protein -- NEURAL DEVELOPMENT AND THE MALIGNANT PROCESS

Kimberly M. Rieger-Christ, Karina L. Brierley and Michael A. Reale

Department of Internal Medicine/Oncology, Yale School of Medicine/West Haven Veterans Administration Medical Center, 333 Cedar St., P.O. Box 208032, New Haven, CT 06520-8032

Received 8/25/97 Accepted 9/5/97

TABLE OF CONTENTS

1. Abstract

2. Introduction

3. DCC and Development

3.1. DCC guides axonal migrations

3.2 DCC guides cell migrations

3.3. Summary

4. DCC and Cancer

4.1. 18q Allelic loss and DCC expression studies

4.2. Experimental approaches

4.3. Summary

5. Perspective

6. Acknowledgments

7. References

2. INTRODUCTION

The DCC (deleted in colorectal cancer) gene was originally identified through studies of the progressive stages of human colorectal tumor development. These studies demonstrated allelic loss involving a region of the long arm of chromosome 18 in approximately 50% of class III adenomas, greater than 70% of carcinomas and nearly 100% of hepatic metastases (1,2). The common region of loss at 18q21.3 was found to contain the extraordinarily large DCC gene (1.35 megabases, 29 exons) (3-4). The sequence of the DCC cDNA predicts a 1447 amino acid transmembrane protein with extracellular immunoglobulin and fibronectin type III domains typical of the neural cell adhesion molecule (NCAM) family of proteins (4-6). DCC and neogenin, a protein whose expression is dynamically regulated in chicken neural development, define an NCAM subfamily on the basis of their unique constellation of extracellular domain motifs (six immunoglobulin and four fibronectin type III domains) and cytoplasmic domain (7). Their approximately 325 amino acid cytoplasmic domains do not share similarity with any other proteins in the data base (Figure 1). Several DCC homologs have been isolated and cloned from both invertebrates and vertebrates (8-12). DCC has been highly conserved in vertebrate evolution as the sequence predicted by the human cDNA shares co-linearity and greater than 75% overall identity at the amino acid level to the cDNA for a Xenopus laevis homologue of DCC (12) (Figure 1).

Figure 1. The DCC family of proteins. Percent identity with human DCC at the amino acid level is represented for each of the three major domains. (TM - transmembrane).

The expression pattern of the DCC gene in adult tissues is informative as levels of expression in the central and peripheral nervous system far exceed those of non-neural tissues (5,6,11,12). Alternative splicing involving both the extracellular and cytoplasmic domains of the DCC protein has been described, though the functional significance of these splicing events is not yet understood (6,11,13).