Biomedical subjects

Lynne M Quarmby

Publications and source records attributed to Lynne M Quarmby.

9 recordsLinked to original sources

PubMed2005

Caught Nek-ing: cilia and centrioles.

The Nek family of cell-cycle kinases is widely represented in eukaryotes and includes numerous proteins that were described only recently and remain poorly characterized. Comparing Neks in the context of clades allows us to examine the question of whether microbial eukaryotic Neks, although not strictly orthologs of their vertebrate counterparts, can provide clues to ancestral functions that might be retained in the vertebrate Neks. Relatives of the Nek2/NIMA proteins play important roles at the G2-M transition in nuclear envelope breakdown and centromere separation. Nek6, Nek7 and Nek9 also seem to regulate mitosis. By contrast, Nek1 and Nek8 have been linked with polycystic kidney disease. Results of statistical analysis indicate that the family coevolved with centrioles that function as both microtubule-organizing centers and the basal bodies of cilia. This evolutionary perspective, taken together with functional studies of microbial Neks, provides new insights into the cellular roles of the proteins and disease with which some of them have been linked.

Animals↗

PubMed2005

NIMA-related kinases defective in murine models of polycystic kidney diseases localize to primary cilia and centrosomes.

A key feature of the polycystic kidney diseases is aberrant cell proliferation, a consequence of dysfunctional ciliary signaling. The NIMA-related kinases (Nek) Nek1 and Nek8 carry the causal mutations of two of the eight established mouse models of polycystic kidneys. Nek proteins have roles in cell cycle and may contribute to coordinate regulation of cilia and cell-cycle progression. Herein is reported that in a mouse kidney epithelial cell line, mNek1 localizes to centrosomes in interphase and remains associated with the mitotic spindle pole during mitosis. In contrast, mNek8 localizes to the proximal region of the primary cilium and is not observed in dividing cells. Knockdown of mNek8 by siRNA does not affect ciliary assembly. Taken together with the phenotypes of the mutant mice, these data suggest that mNek1 and mNek8 provide links between cilia, centrosomes, and cell-cycle regulation.

Animals↗

PubMed2005

A NIMA-related kinase, Cnk2p, regulates both flagellar length and cell size in Chlamydomonas.

The cycle of ciliogenesis and ciliary disassembly is coordinated with cell division. In the unicellular alga Chlamydomonas, the two flagella are maintained at constant and equal length during interphase, and are reabsorbed prior to mitosis. We report that the NIMA-related kinase, Cnk2p, is an axonemal protein that affects flagellar length via effects on disassembly rate and also plays a role in the cellular assessment of size prior to committing to mitosis. This is the second NIMA-related kinase shown to affect ciliary function and cell cycle progression in Chlamydomonas. We speculate that members of the NIMA family have evolved nuanced roles to coordinate cilia/cell cycle regulation.

Animals↗

PubMed2005

Cilia and the cell cycle?

A recent convergence of data indicating a relationship between cilia and proliferative diseases, such as polycystic kidney disease, has revived the long-standing enigma of the reciprocal regulatory relationship between cilia and the cell cycle. Multiple signaling pathways are localized to cilia in mammalian cells, and some proteins have been shown to act both in the cilium and in cell cycle regulation. Work from the unicellular alga Chlamydomonas is providing novel insights as to how cilia and the cell cycle are coordinately regulated.

Animals↗

PubMed2004

A NIMA-related kinase, Fa2p, localizes to a novel site in the proximal cilia of Chlamydomonas and mouse kidney cells.

Polycystic kidney disease and related syndromes involve dysregulation of cell proliferation in conjunction with ciliary defects. The relationship between cilia and cell cycle is enigmatic, but it may involve regulation by the NIMA-family of kinases (Neks). We previously showed that the Nek Fa2p is important for ciliary function and cell cycle in Chlamydomonas. We now show that Fa2p localizes to an important regulatory site at the proximal end of cilia in both Chlamydomonas and a mouse kidney cell line. Fa2p also is associated with the proximal end of centrioles. Its localization is dynamic during the cell cycle, following a similar pattern in both cell types. The cell cycle function of Fa2p is kinase independent, whereas its ciliary function is kinase dependent. Mice with mutations in Nek1 or Nek8 have cystic kidneys; therefore, our discovery that a member of this phylogenetic group of Nek proteins is localized to the same sites in Chlamydomonas and kidney epithelial cells suggests that Neks play conserved roles in the coordination of cilia and cell cycle progression.

Animals↗

PubMed2004

Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous developmental disorder whose molecular basis is largely unknown. Here, we show that mutations in the Caenorhabditis elegans bbs-7 and bbs-8 genes cause structural and functional defects in cilia. C. elegans BBS proteins localize predominantly at the base of cilia, and like proteins involved in intraflagellar transport (IFT), a process necessary for cilia biogenesis and maintenance, move bidirectionally along the ciliary axoneme. Importantly, we demonstrate that BBS-7 and BBS-8 are required for the normal localization/motility of the IFT proteins OSM-5/Polaris and CHE-11, and to a notably lesser extent, CHE-2. We propose that BBS proteins play important, selective roles in the assembly and/or function of IFT particle components. Our findings also suggest that some of the cardinal and secondary symptoms of BBS, such as obesity, diabetes, cardiomyopathy, and learning defects may result from cilia dysfunction.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Cellular deflagellation.

Deciliation, also known as deflagellation, flagellar autotomy, flagellar excision, or flagellar shedding, refers to the process whereby eukaryotic cells shed their cilia or flagella, often in response to stress. Used for many decades as a tool for scientists interested in the structure, function, and genesis of cilia, deciliation itself is a process worthy of scientific investigation. Deciliation has numerous direct medical implications, but more profoundly, intriguing relationships between deciliation, ciliogenesis, and the cell cycle indicate that understanding the mechanism of deciliation will contribute to a deeper understanding of broad aspects of cell biology. This review provides a critical examination of diverse data bearing on this problem. It also highlights current deficiencies in our understanding of the mechanism of deciliation.

Animals↗

PubMed2002

The FA2 gene of Chlamydomonas encodes a NIMA family kinase with roles in cell cycle progression and microtubule severing during deflagellation.

The NIMA kinases are one of several families of kinases that participate in driving the eukaryotic cell cycle. NIMA-related kinases have been implicated in G2/M progression, chromatin condensation and regulation of the centrosome cycle. Here we report the identification of a new member of this family, FA2, from Chlamydomonas reinhardtii. FA2 was originally discovered in a genetic screen for deflagellation-defective mutants. We have previously shown that FA2 is essential for basal-body/centriole-associated microtubule severing. We now report that the FA2 NIMA-related kinase also plays a role in cell cycle progression in Chlamydomonas. This is the first indication that members of the NIMA family might exert their effects through the regulation of microtubule severing.

Amino Acid Sequence↗

PubMedDate not supplied

Identification and sequence analysis of six new members of the NIMA-related kinase family in Chlamydomonas.

The NIMA kinases are an evolutionarily conserved protein family with enigmatic roles in the regulation of mitosis. We report six new members of this family in Chlamydomonas, in addition to the previously identified NIMA-related kinase, Fa2p. Chlamydomonas NIMA-related kinases (CNKs) 1-6 were sequenced from subclones generated by RT-PCR using information from EST libraries and the recently sequenced Chlamydomonas genome. Phylogenetic and bioinformatic approaches were used to determine the relationships of the six new members with known members of the NIMA-related kinase family. Although humans express at least eleven NIMA-related kinases, the eukaryotic microbes that have been studied to date express only one or two members of the family. Thus, the discovery that Chlamydomonas expresses a total of at least seven NIMA-related kinases is intriguing. Our analyses suggest that members of this family may play roles in the assembly and function of cilia.

Amino Acid Sequence↗