Fez1/Lzts1 absence impairs Cdk1/Cdc25C interaction during mitosis and predisposes mice to cancer development.
The FEZ1/LZTS1 (LZTS1) protein is frequently downregulated in human cancers of different histotypes. LZTS1 is expressed in normal tissues, and its introduction in cancer cells inhibits cell growth and suppresses tumorigenicity, owing to an accumulation of cells in G2/M. Here, we define its role in cell cycle regulation and tumor progression by generating Lzts1 knockout mice. In Lzts1(-/-) mouse embryo fibroblasts (MEFs), Cdc25C degradation was increased during M phase, resulting in decreased Cdk1 activity. As a consequence, Lzts1(-/-) MEFs showed accelerated mitotic progression, resistance to taxol- and nocodazole-induced M phase arrest, and improper chromosome segregation. Accordingly, Lzts1 deficiency was associated with an increased incidence of both spontaneous and carcinogen-induced cancers in mice.
Vecchione
Andrea
A
Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
Baldassarre
Gustavo
G
Ishii
Hideshi
H
Nicoloso
Milena S
MS
Belletti
Barbara
B
Petrocca
Fabio
F
Zanesi
Nicola
N
Fong
Louise Y Y
LY
Battista
Sabrina
S
Guarnieri
Daniela
D
Baffa
Raffaele
R
Alder
Hansjuerg
H
Farber
John L
JL
Donovan
Peter J
PJ
Croce
Carlo M
CM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000502:physiology*; D002273:Carcinogens; D018797:Cell Cycle Proteins / Q000502:physiology*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D020090:Chromosome Segregation; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D008969:Molecular Sequence Data; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D020687:cdc25 Phosphatases / Q000502:physiology*
D000970:Antineoplastic Agents; D002273:Carcinogens; D018797:Cell Cycle Proteins; D025521:Tumor Suppressor Proteins; C014707:nitrosobenzylmethylamine; D016203:CDC2 Protein Kinase; C517009:CDC25C protein, human; C517010:Cdc25c protein, mouse; D020687:cdc25 Phosphatases; D004128:Dimethylnitrosamine; D017239:Paclitaxel; D015739:Nocodazole