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.