Do cilia put brakes on the cell cycle?
ABSTRACT Two papers in this issue show that dynein-binding proteins may regulate the G1-S transition through an effect on cilia. Nde1, a known partner of dynein light chain LC8, controls ciliary length in vitro and in zebrafish, and influences the G1-S progression. The phosphorylation of Tctex1, a dynein light chain, modulates cilia length and accelerates G1-S, thereby regulating proliferation-differentiation decisions in the developing mouse neocortex.
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ABSTRACT: Cilia and flagella are dynamic organelles that undergo assembly and disassembly during each cell cycle. They are structurally polarized, and the mechanisms by which these organelles are disassembled are incompletely understood. Here, we show that flagellar resorption occurs in two distinct phases of length-dependent regulation. A CDK-like kinase, encoded by flagellar shortening 1 (FLS1), is required for the normal rate of disassembly of only the distal part of the flagellum. Mechanistically, loss of function of FLS1 prevents the initial phosphorylation of CALK, an aurora-like kinase that regulates flagellar shortening, and induces the earlier onset of the inhibitory phosphorylation of CrKinesin13, a microtubule depolymerase, which is involved in flagellar shortening. In addition, CALK and CrKinesin13 phosphorylation can also be induced by the process of flagellar shortening itself, demonstrating an example of cilia-generated signaling not requiring the binding of a ligand or the stimulation of an ion channel. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.Cell Reports 03/2015; 19(11). DOI:10.1016/j.celrep.2015.02.044 · 7.21 Impact Factor
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ABSTRACT: Protein interaction networks play central roles in biological systems, from simple metabolic pathways through complex programs permitting the development of organisms. Multicellularity could only have arisen from a careful orchestration of cellular and molecular roles and responsibilities, all properly controlled and regulated. Disease reflects a breakdown of this organismal homeostasis. To better understand the evolution of interactions whose dysfunction may be contributing factors to disease, we derived the human protein coevolution network using our MatrixMatchMaker algorithm and using the Orthologous MAtrix project (OMA) database as a source for protein orthologs from 103 eukaryotic genomes. We annotated the coevolution network using protein-protein interaction data, many functional data sources, and we explored the evolutionary rates and dates of emergence of the proteins in our data set. Strikingly, clustering based only on the topology of the coevolution network partitions it into two subnetworks, one generally representing ancient eukaryotic functions and the other functions more recently acquired during animal evolution. That latter subnetwork is enriched for proteins with roles in cell-cell communication, the control of cell division, and related multicellular functions. Further annotation using data from genetic disease databases and cancer genome sequences strongly implicates these proteins in both ciliopathies and cancer. The enrichment for such disease markers in the animal network suggests a functional link between these coevolving proteins. Genetic validation corroborates the recruitment of ancient cilia in the evolution of multicellularity.Molecular Biology and Evolution 09/2012; 30(2). DOI:10.1093/molbev/mss218 · 14.31 Impact Factor
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ABSTRACT: Mutations and/or deletions of Pkd1 in mouse models resulted in attenuation of osteoblast function and defective bone formation; however, the function of PKD1 in human osteoblast and bone remains uncertain. In the current study, we used lentivirus-mediated shRNA technology to stably knock down PKD1 in the human osteoblastic MG-63 cell line and to investigate the role of PKD1 on human osteoblast function and molecular mechanisms. We found that a 53% reduction of PKD1 by PKD1 shRNA in stable, transfected MG-63 cells resulted in increased cell proliferation and impaired osteoblastic differentiation as reflected by increased BrdU incorporation, decreased alkaline phosphatase activity, and calcium deposition and by decreased expression of RUNX2 and OSTERIX compared to control shRNA MG-63 cells. In addition, knockdown of PKD1 mRNA caused enhanced adipogenesis in stable PKD1 shRNA MG-63 cells as evidenced by elevated lipid accumulation and increased expression of adipocyte-related markers such as PPARγ and aP2. The stable PKD1 shRNA MG-63 cells exhibited lower basal intracellular calcium, which led to attenuated cytosolic calcium signaling in response to fluid flow shear stress, as well as increased intracellular cAMP messages in response to forskolin (10 µM) stimulation. Moreover, increased cell proliferation, inhibited osteoblastic differentiation, and osteogenic and adipogenic gene markers were significantly reversed in stable PKD1 shRNA MG-63 cells when treated with H89 (1 µM), an inhibitor of PKA. These findings suggest that downregulation of PKD1 in human MG-63 cells resulted in defective osteoblast function via intracellular calcium-cAMP/PKA signaling pathway.Journal of Cellular Biochemistry 03/2012; 113(3):967-76. DOI:10.1002/jcb.23426 · 3.37 Impact Factor