TGF beta1 induces multiple independent signals to regulate human trophoblastic differentiation: mechanistic insights.
Transforming growth factor-beta 1 (TGF beta1) plays a crucial role in controlling trophoblast growth and invasion. Loss of this key regulatory function provides the pathophysiological basis for several tumors, which are characterized by uncontrolled telomerase activity. We have shown earlier that telomerase activity is negatively regulated during terminal differentiation of human trophoblasts, and that TGF beta1 may be an important factor governing the transcription of human telomerase reverse transcriptase (hTERT) (the catalytic subunit of the telomerase complex) during this process. In the present study, we extend these observations to identify possible functional effectors of TGF beta1-induced loss in telomerase activity during human trophoblastic differentiation. We show that this regulation may involve the suppression of c-Myc and an increased production of Mad1. We also observed a simultaneous increase in the expression of cyclin-dependent-kinase inhibitors, p21, p27, p15 and p16, associated with a loss in expression of Cyclin-A2 and Cyclin-E. Thus, TGF beta1 may induce multiple independent signals to check the proliferative potential of human trophoblastic cells and allow their functional differentiation.
Rama
S
S
Department of Biochemistry and Department of Molecular Reproduction, Development & Genetics, Indian Institute of Science, Bangalore 560 012, Kamataka, India.
Suresh
Y
Y
Rao
A J
AJ
D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000187:drug effects; D019925:Cyclin A / Q000096:biosynthesis; D056751:Cyclin A2; D019927:Cyclin E / Q000096:biosynthesis; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D019098:Telomerase / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014327:Trophoblasts / Q000166:cytology*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
C503721:CCNA2 protein, human; C493956:CDKN1A protein, human; C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D019925:Cyclin A; D056751:Cyclin A2; D019927:Cyclin E; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016271:Proto-Oncogene Proteins c-myc; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D019098:Telomerase