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Tudor and Nuclease-Like Domains Containing Protein p100 Function as Coactivators for Signal Transducer and Activator of Transcription 5

Haartman Institute (K.P., O.S.), Department of Virology, and Biomedicum Helsinki (K.P., O.S.), Programme for Developmental and Reproductive Biology, FIN-00014 University of Helsinki, Helsinki, Finland; Institute of Medical Technology (J.Y., O.S.), University of Tampere; and Department of Clinical Microbiology (O.S.), Tampere University Hospital, FIN-33014 Tampere, Finland

Address all correspondence and requests for reprints to: Olli Silvennoinen, Biomedicum Helsinki, Programme for Developmental and Reproductive Biology, Haartmaninkatu 8, P.O. Box 63, FIN-00014 University of Helsinki, Helsinki, Finland.

Signal transducer and activator of transcription 5 (Stat5) plays a critical role in prolactin (PRL)-induced transcription of several milk protein genes. Stat5-mediated gene regulation is modulated by cooperation of Stat5 with cell type- and promoter-specific transcription factors as well as by interaction with transcriptional coregulators. Recently, the expression of a tudor and staphylococcal nuclease-like domains containing protein p100 was found to be increased in mammary epithelial cells during lactation in response to lactogenic hormones. p100 was initially identified as a transcriptional coactivator of the Epstein-Barr virus nuclear antigen 2. In this study we investigated the potential role of p100 in PRL-induced Stat5-mediated transcriptional activation. PRL stimulation increased the p100 protein levels in HC11 mouse mammary epithelial cells. p100 did not affect the early activation events of Stat5, but p100 enhanced the Stat5-dependent transcriptional activation in HC11 cells. p100 associated with Stat5 both in vivo and in vitro, and the interaction was mediated by both the tudor and staphylococcal nuclease-like domains of p100. Together these results suggest that p100 functions as a transcriptional coactivator for Stat5-dependent gene regulation and the existence of a positive regulatory loop in PRL-induced transcription, in which PRL stabilizes p100 protein, which in turn can cooperate with Stat5 in transcriptional activation.

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