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Submitted on October 19, 2004
Accepted on January 24, 2005
Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), Montréal QC Canada H2W 1R7
* To whom correspondence should be addressed. E-mail: jacques.drouin{at}ircm.qc.ca.
The signaling molecules BMP4 and BMP2 have been implicated in early organogenesis and cell differentiation of the pituitary. However, the use of different experimental paradigms has led to conflicting interpretations with regards to the action of these factors on differentiation of corticotroph cells and on expression of the pro-opiomelanocortin (POMC) gene. We have now directly assessed the action of BMP signaling on POMC expression and found that BMP4 represses POMC mRNA levels and promoter activity. This repression appears to be dependent on the classical BMP signaling pathway that involves the Alk3/6 receptors and the Smad1/4 transcription factors. The repression is reversed by overexpression of the inhibitory Smads, Smad6 or Smad7. Collectively, the evidence suggests that autocrine BMP signaling may be acting upon AtT-20 cells to set the level of POMC expression. Upon BMP4 stimulation, activated phospho-Smad1 is recruited to the POMC promoter where it apparently acts through interactions with the Pitx and Tpit transcription factors. It is postulated that these interactions interfere with the transcriptional activity of Pitx and/or Tpit, thus resulting in transcriptional repression.
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