Identification of rCop-1, a New Member of the CCN Protein Family, as a Negative Regulator for Cell Transformation

ABSTRACT

By using a model system for cell transformation mediated by the cooperation of the activated H-ras oncogene and the inactivated p53 tumor suppressor gene, rCop-1 was identified by mRNA differential display as a gene whose expression became lost after cell transformation. Homology analysis indicates that rCop-1 belongs to an emerging cysteine-rich growth regulator family called CCN, which includes connective-tissue growth factor, CYR61, CEF10 (v-src inducible), and the product of the nov proto-oncogene. Unlike the other members of the CCN gene family, rCop-1 is not an immediate-early gene, it lacks the conserved C-terminal domain which was shown to confer both growth-stimulating and heparin-binding activities, and its expression is lost in cells transformed by a variety of mechanisms. Ectopic expression of rCop-1 by retroviral gene transfers led to cell death in a transformation-specific manner. These results suggest that rCop-1 represents a new class of CCN family proteins that have functions opposing those of the previously identified members.

ACKNOWLEDGMENTS

We are grateful to A. J. Levine for providing the REFs and A1-5 and T101-4 cells. We also thank L. F. Lau for generously providing the cyr61 cDNA, G. Dranoff for supplying the pMFG retroviral vector and advice on retroviral infection, and R. Wisdom for making available the pBabe retroviral vector.

This work was supported in part by grants from the American Cancer Society and the National Institutes of Health (CA74067 and CA68485).