MDM1 is a microtubule-binding protein that negatively regulates centriole duplication.
Mouse double-minute 1 (Mdm1) was originally identified as a gene amplified in transformed mouse cells and more recently as being highly up-regulated during differentiation of multiciliated epithelial cells, a specialized cell type having hundreds of centrioles and motile cilia. Here we show that the MDM1 protein localizes to centrioles of dividing cells and differentiating multiciliated cells. 3D-SIM microscopy showed that MDM1 is closely associated with the centriole barrel, likely residing in the centriole lumen. Overexpression of MDM1 suppressed centriole duplication, whereas depletion of MDM1 resulted in an increase in granular material that likely represents early intermediates in centriole formation. We show that MDM1 binds microtubules in vivo and in vitro. We identified a repeat motif in MDM1 that is required for efficient microtubule binding and found that these repeats are also present in CCSAP, another microtubule-binding protein. We propose that MDM1 is a negative regulator of centriole duplication and that its function is mediated through microtubule binding.
Department of Biology, Stanford University, Stanford, CA 94305.
Daniel
D
Van de Mark
Laboratory of Protein Dynamics and Signaling, Center for Cancer Research-Frederick, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
Dong
D
Kong
Laboratory of Protein Dynamics and Signaling, Center for Cancer Research-Frederick, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
Jadranka
J
Loncarek
Department of Biology, Stanford University, Stanford, CA 94305 Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA 94305 stearns@stanford.eu.
Tim
T
Stearns
D020816:Amino Acid Motifs; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002502:Centrioles / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism; D002923:Cilia / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering