Disease relevance of CDC12

• Expression of Nedd5, a mammalian septin, in human brain tumors [1].
• An RNA-Binding Protein, hnRNP A1, and a Scaffold Protein, Septin 6, Facilitate Hepatitis C Virus Replication [2].

High impact information on CDC12

• Siz1 is required for SUMO attachment to the S. cerevisiae septins in vivo and strongly stimulates septin sumoylation in vitro [3].
• Sec3-GFP localization is independent of secretory pathway function, of the actin and septin cytoskeletons, and of the polarity establishment proteins [4].
• Plasma membrane compartmentalization in yeast by messenger RNA transport and a septin diffusion barrier [5].
• Higher-order septin assemblies represented by the yeast septin collar function as cytoskeleton, providing structural support and scaffolds for many cellular factors [6].
• Recent studies revealed that septin populations with no obvious structure that had previously escaped our attention serve as scaffolds for kinetochore motor proteins and as sequestering depots for microtubule regulators [6].

Biological context of CDC12

• Interestingly, a cdc5Delta bfa1Delta swe1Delta triple mutant is viable but grows slowly, whereas cdc5Delta cells bearing both CDC5DeltaC-CNM67 and CDC5DeltaC-CDC12 grow well with only a mild cell cycle delay [7].
• The second suppressor maps to the right arm of chromosome VIII distal to CDC12 and is REC104, a meiosis-specific gene believed to act early in meiosis [8].
• Cla4 and Ste20 kinases apparently share a function in localizing cell growth with respect to the septin ring [9].
• Thus, septin collar formation may correspond to septin filament assembly, and requires both GTP binding and Cla4-mediated phosphorylation of septins [10].
• In vivo, mutants unable to bind GTP prevent septin collar formation, whereas mutants that block GTP hydrolysis do not [10].

Anatomical context of CDC12

• Examination of mating cells and cells responding to purified mating pheromone revealed novel arrangements of the CDC3 and CDC12 products in the regions of cell wall reorganization [11].
• Our results suggest that polarisome components and Cla4p are required for the initial assembly of the septin ring and that the actin cytoskeleton is involved in this process [12].
• Thus, placement of the Int1p/septin ring with respect to the mother-daughter cell junction distinguishes yeast/pseudohyphal growth from hyphal growth in C. albicans [13].
• Using a septin-GFP fusion and time-lapse confocal microscopy, we have determined that septin dynamics are maintained in budding zygotes and during unipolar synchronous growth in pseudohyphae [14].
• Budding cells of the yeast Saccharomyces cerevisiae possess a ring of septin filaments of unknown biochemical nature that lies under the inner surface of the plasma membrane in the neck that connects the mother cell to its bud [15].

Associations of CDC12 with chemical compounds

• Consistently, treatment of cla4Delta mutant with the actin inhibitor latrunculin A inhibited septin ring assembly [12].
• The septin polypeptides show various degrees of saturation with guanine nucleotides in different complexes [16].
• Glutaraldehyde-fixed rat brain sec6/8 complex adopts a conformation resembling the letter "T" or "Y". The sec6/8 and septin complexes likely play an important role in trafficking vesicles and organizing proteins at the plasma membrane of neurons [17].
• In this pathway, insults affecting the actin or septin cytoskeleton trigger a cell cycle arrest, mediated by the Wee1 homolog Swe1p, which catalyzes the inhibitory phosphorylation of the mitosis-promoting cyclin-dependent kinase (CDK) on a conserved tyrosine residue [18].
• Both localizations are septin-independent and disrupted by treatment with filipin [19].

Physical interactions of CDC12

• To investigate the relationship between these filaments and the neck filaments, we purified septin complexes from cells deleted for CDC10 or CDC11 [20].
• In addition, Cdc11 forms a stoichiometric complex with Cdc12, independent of its CTE [21].
• Candida albicans Int1p interacts with the septin ring in yeast and hyphal cells [13].
• Shs1p: a novel member of septin that interacts with spa2p, involved in polarized growth in saccharomyces cerevisiae [22].
• Afr1p interacts with Cdc12p, which belongs to a family of filament-forming proteins termed septins that have been studied primarily for their role in bud morphogenesis and cytokinesis [23].

Enzymatic interactions of CDC12

• Cells lacking functional Ndc10p show defects in spindle stability during anaphase and failure to split the septin ring during cytokinesis [24].

Regulatory relationships of CDC12

• This defect is greatly exacerbated when combined with GTP binding-defective septins; conversely, the septin collar assembly defect of such mutants is suppressed efficiently by CLA4 overexpression [10].
• Septin recruitment depends on activated Cdc42p but not on the normal pathway for bud-site selection [25].
• Apical polarization was delayed in cdc15 mutants as compared with budding in control cells and this delay was abolished in a septin mutant [26].
• Specifically, we show that septin ring separation and disassembly is delayed in anaphase, suggesting that CBF3 regulates septin dynamics [27].
• In addition to localizing at the spindle poles and cytokinetic neck filaments, Cdc5 induces and localizes to additional septin ring structures within the elongated buds [28].

Other interactions of CDC12

• However, double cla4 ste20 mutants cannot maintain septin rings at the bud neck and cannot undergo cytokinesis [9].
• We also used the CDC3-specific and CDC12-specific antibodies to investigate the timing of localization of these proteins to the budding site [11].
• GTP binding-defective Cdc10 and Cdc12 form soluble heteromeric complexes with other septins both in yeast and in bacteria; yet, unlike wild-type, mutant complexes do not bind GTP and do not assemble into filaments in vitro [10].
• A search for additional S. cerevisiae septin genes using the polymerase chain reaction identified SPR3, a gene that had been identified previously on the basis of its sporulation-specific expression [29].
• In contrast, mutations affecting the other two Nim1p-related kinases in S. cerevisiae, Hsl1p and Kcc4p, produce no detectable effect on septin organization [30].

Analytical, diagnostic and therapeutic context of CDC12

• We showed previously by immunofluorescence that the CDC12 gene product is probably a constituent of the ring of 10-nm filaments (Haarer, B. and J. Pringle. 1987. Mol. Cell. Biol. 7:3678-3687) [11].
• The septin cytoskeleton assembles at the pre-bud site before bud emergence, remains there during bud growth and duplicates at late mitosis eventually disappearing after cell separation [14].
• Using indirect immunofluorescence, we show that cdc12p is located in the cell division ring and not in other actin structures [31].
• Molecular dissection of a yeast septin: distinct domains are required for septin interaction, localization, and function [32].
• We also demonstrate that Kcc4 associates with septin proteins in vitro and in vivo by two-hybrid analysis, GST pull-down experiments, immunoprecipitation, and analysis of direct association with affinity-purified GST-Kcc4 and MBP-Septin proteins [33].

References