Prolyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer.
Phosphorylation of proteins on serine or threonine residues preceding proline (Ser/Thr-Pro) is a major intracellular signaling mechanism. The phosphorylated Ser/Thr-Pro motifs in a certain subset of phosphoproteins are isomerized specifically by the peptidyl-prolyl cis-trans isomerase Pin1. This post-phosphorylation isomerization can lead to conformational changes in the substrate proteins and modulate their functions. Pin1 interacts with a number of mitotic phosphoproteins, and plays a critical role in mitotic regulation. Recent work indicates that Pin1 is overexpressed in many human cancers and plays an important role in oncogenesis. Pin1 regulates the expression of cyclin D1 by cooperating with Ras signaling and inhibiting the interaction of beta-catenin with the tumor suppressor APC and also directly stabilizing cyclin D1 protein. Furthermore, PIN1 is an E2F target gene essential for the Neu/Ras-induced transformation of mammary epithelial cells. Pin1 is also a critical regulator of the tumor suppressor p53 during DNA damage response. Given its role in cell growth control and oncogenesis, Pin1 could represent a new anti-cancer target.
Ryo
Akihide
A
Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Liou
Yih-Cherng
YC
Lu
Kun Ping
KP
Wulf
Gerburg
G
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002384:Catalysis; D019938:Cyclin D1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000502:physiology; D004249:DNA Damage; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051176:beta Catenin
D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D019938:Cyclin D1; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase