The essential similarity of TGFbeta and activin receptor transcriptional responses in cancer cells.
The binding of activin and TGFbeta 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 tumorsuppressive 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 TGFbeta type I (ALK5m) receptors and by variation of Smad4 expression in cancer cells. Eleven of 15 previously reported TGFbeta 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 TGFbeta and activin tumor-suppressor effects, many downstream genes have not yet been evaluated for a suppressive role. A high similarity of TGFbeta 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.
Department of Oncology, The Johns Hopkins Medical Institutions; Baltimore, Maryland 21231, USA.
Byungwoo
B
Ryu
Scott E
SE
Kern
D030201:Activin Receptors, Type I / Q000235:genetics*; D000256:Adenoviridae / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I