PIN1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells

Akihide Ryo, Yih Cherng Liou, Gerburg Wulf, Masafumi Nakamura, Sam W. Lee, Kun Ping Lu

Research output: Contribution to journalArticle

200 Citations (Scopus)

Abstract

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 knock-out 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.

Original languageEnglish
Pages (from-to)5281-5295
Number of pages15
JournalMolecular and cellular biology
Volume22
Issue number15
DOIs
Publication statusPublished - Jul 22 2002
Externally publishedYes

Fingerprint

erbB-2 Genes
Cyclin D1
Essential Genes
Breast
Epithelial Cells
Threonine
Proline
Serine
Phosphorylation
Breast Neoplasms
E2F Transcription Factors
Peptidylprolyl Isomerase
Phenotype
Amino Acid Motifs
Oncogenes
Knockout Mice
Transcriptional Activation
Carcinogenesis
Up-Regulation
Pregnancy

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

PIN1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells. / Ryo, Akihide; Liou, Yih Cherng; Wulf, Gerburg; Nakamura, Masafumi; Lee, Sam W.; Lu, Kun Ping.

In: Molecular and cellular biology, Vol. 22, No. 15, 22.07.2002, p. 5281-5295.

Research output: Contribution to journalArticle

Ryo, Akihide ; Liou, Yih Cherng ; Wulf, Gerburg ; Nakamura, Masafumi ; Lee, Sam W. ; Lu, Kun Ping. / PIN1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells. In: Molecular and cellular biology. 2002 ; Vol. 22, No. 15. pp. 5281-5295.
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