Phosphorylation-dependent proline isomerization catalyzed by Pin1 is essential for tumor cell survival and entry into mitosis.
Pin1, a member of the parvulin family of peptidyl-prolyl cis-trans isomerases (PPIases) has been implicated in the G2-M transition of the mammalian cell cycle. Pin1 interacts with a series of mitotic phosphoproteins, including Polo-like kinase-1, Cdc25C, and Cdc27, and is thought to act as a phosphorylation-dependent PPIase for these target molecules. Pin1 recognizes phosphorylated serine-proline or threonine-proline peptide-bonds in test substrates up to 1300-fold better than in the respective unphosphorylated peptides. To test directly whether Pin1 regulates the G2-M transition and/or progression through mitosis by catalyzing phosphorylation-dependent prolyl isomerization of essential mitotic targets, we examined the consequences of Pin1 depletion, achieved by (a) overexpression of Pin1 antisense RNA, (b) overexpression of dominant-negative Pin1, and (c) by a known small-molecule Pin1-PPIase inhibitor, juglone. The results of all of the three lines of investigation show that the catalytic activity of Pin1 is essential for tumor cell survival and entry into mitosis.
Rippmann
J F
JF
Department of Oncology Research, Boehringer Ingelheim Pharma KG, Biberach, Germany.
Hobbie
S
S
Daiber
C
C
Guilliard
B
B
Bauer
M
M
Birk
J
J
Nar
H
H
Garin-Chesa
P
P
Rettig
W J
WJ
Schnapp
A
A
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002384:Catalysis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D007399:Interphase; D007700:Kinetics; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011392:Proline / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D002843:Chromatin; D004791:Enzyme Inhibitors; D006657:Histones; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D011993:Recombinant Fusion Proteins; D011392:Proline; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; D017239:Paclitaxel; C005134:juglone