PIN1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells.
Oncogenes Neu/HER2/ErbB2 and Ras can induce mammary tumorigenesis via upregulation of cyclin D1. One major regulatory mechanism in these oncogenic signaling pathways is phosphorylation of serines or threonines preceding proline (pSer/Thr-Pro). Interestingly, the pSer/Thr-Pro motifs in proteins exist in two completely distinct cis and trans conformations, whose conversion is catalyzed specifically by the essential prolyl isomerase Pin1. By isomerizing pSer/Thr-Pro bonds, Pin1 can regulate the conformation and function of certain phosphorylated proteins. We have previously shown that Pin1 is overexpressed in breast tumors and positively regulates cyclin D1 by transcriptional activation and posttranslational stabilization. Moreover, in Pin1 knockout mice, mammary epithelial cells fail to undergo massive proliferation during pregnancy, as is the case in cyclin D1 null mice. These results indicate that Pin1 is upregulated in breast cancer and may be involved in mammary tumors. However, the mechanism of Pin1 overexpression in cancer and its significance in cell transformation remain largely unknown. Here we demonstrate that PIN1 expression is mediated by the transcription factor E2F and enhanced by c-Neu and Ha-Ras via E2F. Furthermore, overexpression of Pin1 not only confers transforming properties on mammary epithelial cells but also enhances the transformed phenotypes of Neu/Ras-transformed mammary epithelial cells. In contrast, inhibition of Pin1 suppresses Neu- and Ras-induced transformed phenotypes, which can be fully rescued by overexpression of a constitutively active cyclin D1 mutant that is refractory to the Pin1 inhibition. Thus, Pin1 is an E2F target gene that is essential for the Neu/Ras-induced transformation of mammary epithelial cells through activation of cyclin D1.
Ryo
Akihide
A
Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
Liou
Yih-Cherng
YC
Wulf
Gerburg
G
Nakamura
Masafumi
M
Lee
Sam W
SW
Lu
Kun Ping
KP
D001483:Base Sequence; D001940:Breast / Q000166:cytology / Q000378:metabolism; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005799:Genes, Dominant; D006801:Humans; D008969:Molecular Sequence Data; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D019938:Cyclin D1; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D018631:ras Proteins; C000606846:PIN1 protein, human; C000606850:Pin1 protein, mouse