Gm. Wulf et al., Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1, EMBO J, 20(13), 2001, pp. 3459-3472
Phosphorylation on serines or threonines preceding proline (Ser/Thr-Pro) is
a major signaling mechanism. The conformation of a subset of phosphorylate
d Ser/Thr-Pro motifs is regulated by the prolyl isomerase Pin1, Inhibition
of Pin1 induces apoptosis and may also contribute to neuronal death in Alzh
eimer's disease. However, little is known about the role of Pin1 in cancer
or in modulating transcription factor activity. Here we report that Pin1 is
strikingly overexpressed in human breast cancers, and that its levels corr
elate with cyclin D1 levels in tumors. Overexpression of Pin1 increases cel
lular cyclin D1 protein and activates its promoter. Furthermore, Pin1 binds
c-Jun that is phosphorylated on Ser63/73-Pro motifs by activated JNK or on
cogenic Ras, Moreover, Pin1 cooperates with either activated Ras or JNK to
increase transcriptional activity of c-Jun towards the cyclin D1 promoter.
Thus, Pin1 is up-regulated in human tumors and cooperates with Ras signalin
g in increasing c-Jun transcriptional activity towards cyclin D1, Given the
crucial roles of Ras signaling and cyclin D1 overexpression in oncogenesis
, our results suggest that overexpression of Pin1 may promote tumor growth.