We have identified two related genes whose mRNAs are increased after treatment with transforming growth factor-beta (TGF-beta 1). Mouse AKR-2B cells were treated with TGF-beta 1 in the presence of cyclohexamide and a cDNA library was subjected to differential screening. Several TGF-beta-induced genes (beta IG) were isolated and two of these, beta IG-M1 and beta IG-M2, were characterized. beta IG-M1 and beta IG-M2 RNAs were significantly increased after TGF-beta 1 treatment and both were superinduced in the presence of cyclohexamide. cDNA sequence analysis of beta IG-M1 showed that it encoded a 379-amino-acid protein which was 81% homologous to CEF-10, a v-src and TPA-inducible gene, and identical to cyr61, a gene induced by serum in growth-arrested BALB-3T3 cells. cDNA sequence analysis of beta IG-M2 showed that it encoded a 348-amino-acid protein that was 50% homologous to beta IG-M1. Thirty-eight cysteine residues are conserved between beta IG-M1 and beta IG-M2, which are clustered at the amino and carboxy ends: The middle regions of the two proteins are cysteine free and display the highest degree of nonhomology. Both proteins contain an amino-terminal cysteine-rich motif common to insulin-like growth factor binding proteins and a carboxy-terminal domain with strong homology to a motif found near the carboxy-terminal of the malarial circumsporozoite protein which may be involved in cell adhesion. The regulation of mRNA encoding these proteins by TGF-beta 1 suggests that they may be involved in mediating some of the pleiotropic effects of this multipotent modulator of cell growth and differentiation.