Proto-oncogenes are a cohort of cellular genes which are avidly conserved across a broad span of vertebrate evolution. Evidence now exists that these genes play a role in normal cellular processes such as growth and differentiation. In addition, considerable circumstantial evidence exists linking various alterations in these genes to the induction and/or maintenance of human malignancies. We have been involved in the study of the expression of proto-oncogenes in physiologic states (murine development) and pathologic states (human malignancies). We propose to continue this work using reagents generated in our laboratory during the preceeding funding period, as well as reagents from other laboratories. The general approach is multifaceted, and is as follows. Firstly, we will attempt to obtain information on some aspects of the biologic properties and functions of those proto-oncogenes for which we have useful reagents (i.e., N-myc, c-myb, and c-fos); secondly, we plan to conduct studies on the time-related and tissue-specific expression of these and other proto-oncogenes during murine development; thirdly, we will expand previous studies on the role of the N-myc, c-myb and HER-2/neu proto-oncogenes in specific human malignancies (i.e., neuroblastoma and small cell carcinoma of the lung, acute leukemias, and carcinoma of the breast, respectively); and finally, we propose to conduct a survey of common human malignancies for alterations in proto-oncogenes at the DNA level and/or their expression at the RNA and protein levels, in an attempt to correlate any observed alterations with specific tumor types, or with various clinical parameters of a given tumor.