Philipp Lachenmann: DELPHI Rationale


Schoeller Junkmann Preis 2002

Dr. Judith Müller

Abteilung Experimentelle Gynäkologie und Geburtshilfe, Zentrum für Klinische Forschung, Universitäts-Frauenklinik Freiburg

The transcriptional coactivator FHL2 transmits Rho signals from the cell membrane into the nucleus

The selective expression of target genes by transcription factors such as nuclear receptors does not only require the recruitment of multiple cofactors but also the control of their activity by signalling pathways. How these individual proteins are regulated is an interesting theme of current research.

FHL2 is a LIM-only coactivator of the androgen receptor with an unique tissue-specific expression pattern. In the epithelial cells of the prostate FHL2 colocalizes with the androgen receptor. FHL2 binds specifically to the AR in vitro and in vivo and selectively increases the transcriptional activity of the AR in an agonist dependent manner.

Interestingly, FHL2 is not exclusively nuclear as expected for transcriptional coactivators, but was found to be nuclear, cytoplasmic and in focal adhesions. To elucidate whether nuclear translocation of FHL2 is regulated by extracellular signals we assayed the Rho signalling pathway. GTPases of the Rho family transduce extracellular signals and control cellular processes such as organisation of the actin cytoskeleton, motility, adhesion and gene regulation.

Bioactive sphingolipids or overexpression of Rho family members in tumorigenesis and metastases can activate the Rho signalling pathway. Our results demonstrate that stimulation of the Rho signalling pathway induces translocation of FHL2 to the nucleus and subsequent activates FHL2- and androgen receptor-dependent genes. FHL2 activation is mediated by Rho GTPases, but not by the GTPases Cdc42, Rac1, or Ras, and depends on Rho-kinase. Importantly, prostate tumors do not only overexpress Rho GTPases but also display an altered cellular localisation of FHL2 concomitant with tumor dedifferentiation.

In addition, Rho signalling also influences other transcriptional coactivators thus pointing to a general regulatory role of Rho GTPases in cofactor function. In summary, our data propose a previously undescribed signalling pathway in which the coactivator FHL2 acts as a novel molecular transmitter of the Rho signalling pathway, thereby integrating extracellular cues into altered gene expression.

Müller, J. M., Metzger, E., Greschik, H., Bosserhoff, A.-K., Mercep, L., Buettner, R., and Schüle, R. (2002) EMBO J. 21, 736-748.



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