Leukemia Research Vol. 10. No. 7, p. 931, 1986. 0145-2126/86 $3.{)0 + .00 Printed in Great Britain. Pergamon Journals Ltd.

ABSTRACT

PROTO-ONCOGENES: ROLE IN DEVELOPMENT, GROWTH AND DIFFERENTIATION

I. M. VERMA

Molecular Biology and Virology Laboratory, The Salk Institute, San Diego, CA 92138, U.S.A.

(Accepted 6 February 1986)

THE ACUTELY oncogenic retroviruses encode sequences which are specifically responsible for the morphological transformation of cells in vitro and the induction of neoplasia in vioo. FBJ and FBR.MSV, two murine sarcoma viruses isolated from a spontaneous and a 9°Sr induced osteosarcoma, contain the oncogenefos. Proto- oncogenes, the cellular homologues of the viral trans- forming genes, are expressed in a stage- and tissue- specific manner during prenatal development of the mouse. The proto-oncogenes c-los and c-fms are expressed at the highest levels in extraembryonal tissues, while others like c-abl accumulate at high levels during mid-gestation (day 10-11). Homologues of c- ras m are expressed at all stages of prenatal devel- opment, while transcripts of oncogene mos were not detected at any stage. Such differential expression is indicative of the role during development. Tissue- specific expression was also detected in postnatal tissues.

When quiescent fibroblastic cells are stimulated with growth factors or mitogens, both c-fos and c-myc genes are expressed transiently. Expression of the c-los gene precedes that of c-myc; maximum induction occurs in 20-30 min after stimulation, and expression is shut off by 120min. The c-fos protein, which is extensively

modified and nuclear in location, is expressed transi- ently. Transient expression of the c-los gene is also observed when a rat pheochromocytoma cell line (PC12) is induced to differentiate in response to either nerve growth factor (NGF) , cyclic AMP or K ÷, but not upon addition of dexamethasone. Rapid and transient expression of c-fos gene is also observed following hepa- tectomy or stimulation of T and B cells with mitogens.

Rapid expression of the c-fos gene transcripts is observed when monocytic or monomyelocytic cell lines are induced to differentiate into microphages. No c-los expression can be witnessed when monomyelocytic cells differentiate to granulocytic lineage. A 20-fold induc- tion of c-fos m R N A occurs within 30 min of addition of the inducer TPA, which decreases by 4-5 fold by 60 min and remains constitutive for the next 96-105 h when 99% of the monocytes differentiate to adhering mature macrophages. However, c-fos protein is synthesized only for 60-120 min. Since sustained amounts of c-fos protein can induce transformation, the cell has devised a mechanism to shut off its synthesis without termination of transcripts. The implication of these findings in relation to the role of proto-oncogenes during normal metabolic processes of a cell will be discussed.

931