Function of Drg1/Rit42 in p53-dependent mitotic spindle checkpoint.
Mutations in the Drg1/RTP/Rit42 gene are commonly identified in hereditary neuropathies of the motor and sensory systems. This gene was also identified as a p53 target gene and a differentiation-related, putative metastatic suppressor gene in human colon and prostate cancer. In this study, we show that the Rit42 protein is a microtubule-associated protein that localizes to the centrosomes and participates in the spindle checkpoint in a p53-dependent manner. When ectopically expressed and exposed to spindle inhibitors, Rit42 inhibited polyploidy in several p53-deficient tumor cell lines and increased the population of cells in mitotic arrest. Blocking endogenous Rit42 expression by small interfering RNA in normal human mammary epithelial cells resulted in the disappearance of astral microtubules, and dividing spindle fiber formation was rarely detected. Moreover, these cells underwent microtubule inhibitor-induced reduplication, leading to a polyploidy state. Our findings imply that Rit42 plays a role in the regulation of microtubule dynamics and the maintenance of euploidy.
Kim
Kyung-Tae
KT
Cancer Biology Program, Hematology and Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
Ongusaha
Pat P
PP
Hong
Young-Kwon
YK
Kurdistani
Siavash K
SK
Nakamura
Masafumi
M
Lu
Kun Ping
KP
Lee
Sam W
SW
D000256:Adenoviridae / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000648:ultrastructure; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D009154:Mutation; D015739:Nocodazole / Q000494:pharmacology; D011003:Ploidies; D011123:Polyploidy; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015739:Nocodazole; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000099259:N-myc Downstream-Regulated Gene 1 Protein