The essential similarity of TGF and activin receptor transcriptional responses in cancer cells

The binding of activin and TGF to their respective receptors initiates signals that are carried by common intermediates (Smad proteins) to induce transcriptional activation of downstream genes. Mutations in tumors indicate that both receptor types convey tumor-suppressive signals, among other biologic roles, but their respective sets of transcriptional targets (transcriptomes) and the shared degree of transcriptome similarity are not well explored in these cells. Transcriptome changes were analyzed by gene expression profiling after expression of constitutively active activin type I (ALK4m) and TGF type I (ALK5m) receptors and by variation of Smad4 expression in cancer cells. Eleven of 15 previously reported TGF downstream genes were confirmed to be responsive to TGFb and activin receptors in cancer cells. Expression profiling detected eight of these 11, as well as 13 new Smad4-dependent transcripts. Although Smad4-dependent CDKN1A/p21 induction represents the sole known effector of TGF and activin tumor-suppressor effects, many downstream genes have not yet been evaluated for a suppressive role. A high similarity of TGF and activin responses among the known and new transcriptional target genes indicated an essential redundancy of the two related inputs. This similarity helps relate the mutations seen in both receptor systems and their Smad mediators in human cancers.