A PHO80-like Cyclin and a B-type Cyclin Control the Cell Cycle of the Procyclic Form of Trypanosoma brucei

Li, Ziyin; Wang, Ching C.

doi:10.1074/jbc.m301635200

Cited by 82 publications

(156 citation statements)

References 31 publications

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“…The cell cycle blockade resulted from CRK3 depletion led to an accumulation of zoids in the procyclic form, but only an enrichment of cells with multinucleated aggregates and multiple kinetoplasts was observed in the bloodstream form. This outcome not only reiterates the previous observations from cyclin knockdown studies (11,12) but also reveals an important role of CRK3 in completing the mitosis required for cell division in the bloodstream form but apparently not in the procyclic form. There is thus a difference in the mechanisms of regulating cell division between the two developmental forms of trypanosome.…”

Section: From the Department Of Pharmaceutical Chemistry University supporting

confidence: 77%

“…By using immunoprecipitation and yeast two-hybrid screen, CRK3 from T. brucei was found associated with the PHO80-like CycE1/CYC2 to form a p12 Cks1 -binding cyclin-kinase complex and with a mitotic cyclin homologue CycB2/CYC6 to form a p13 Cks1 -binding complex (12). CycE1/CYC2 was identified by RNA i to be the essential cyclin regulating G 1 /S transition in procyclic form (11), whereas CycB2/CYC6 was the indispensable cyclin in controlling G 2 /M passage in both forms of trypanosome (11,12). These data may agree with the conclusion that formation of a CRK3-CycB2/CYC6 complex is required for initiating passage through the G 2 /M checkpoint in both procyclic (11) and bloodstream (12) forms of T. brucei.…”

Section: Discussionmentioning

confidence: 99%

“…CycE1/CYC2 was identified by RNA i to be the essential cyclin regulating G 1 /S transition in procyclic form (11), whereas CycB2/CYC6 was the indispensable cyclin in controlling G 2 /M passage in both forms of trypanosome (11,12). These data may agree with the conclusion that formation of a CRK3-CycB2/CYC6 complex is required for initiating passage through the G 2 /M checkpoint in both procyclic (11) and bloodstream (12) forms of T. brucei. But formation of the CRK3-CycE1/CYC2 complex is apparently not playing an important role in passing the cells across G 1 /S, because results from the present study showed that a knockdown of CRK3 did not arrest the cells of either form in the G 1 phase.…”

Section: Discussionmentioning

confidence: 99%

“…There are four PHO80 cyclin homologues, three B-type mitotic cyclin homologues, but no G 1 cyclin homologue in the genome of T. brucei (11). In the procyclic form of trypanosome, one of the PHO80 homologues CycE1/CYC2 plays an essential role in controlling the G 1 /S passage, whereas the transition through G 2 /M is regulated by a single B-type mitotic cyclin CycB2/CYC6 (11).…”

Section: From the Department Of Pharmaceutical Chemistry University mentioning

confidence: 99%

“…In the procyclic form of trypanosome, one of the PHO80 homologues CycE1/CYC2 plays an essential role in controlling the G 1 /S passage, whereas the transition through G 2 /M is regulated by a single B-type mitotic cyclin CycB2/CYC6 (11). By using the technique of RNA interference (RNA i ) in T. brucei, depletion of CycE1/CYC2 resulted in an enrichment of slender-shaped anucleated zoids, whereas a reduced CycB2/CYC6 level led to an enhanced population of stumpy-shaped zoids (11). These results reiterated that, in the procyclic form, the kinetoplast cycle alone can drive the cells blocked in S N or mitosis through cytokinesis to cell division.…”

Section: From the Department Of Pharmaceutical Chemistry University mentioning

confidence: 99%

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The Involvement of Two cdc2-related Kinases (CRKs) in Trypanosoma brucei Cell Cycle Regulation and the Distinctive Stage-specific Phenotypes Caused by CRK3 Depletion

Wang

2004

Journal of Biological Chemistry

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106

182

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Cyclin-dependent protein kinases are among the key regulators of eukaryotic cell cycle progression. Potential functions of the five cdc2-related kinases (CRK) in Trypanosoma brucei were analyzed using the RNA interference (RNA i ) technique. In both the procyclic and bloodstream forms of T. brucei, CRK1 is apparently involved in controlling the G 1 /S transition, whereas CRK3 plays an important role in catalyzing cells across the G 2 /M junction. A knockdown of CRK1 caused accumulation of cells in the G 1 phase without apparent phenotypic change, whereas depletion of CRK3 enriched cells of both forms in the G 2 /M phase. However, two distinctive phenotypes were observed between the CRK3-deficient procyclic and bloodstream forms. The procyclic form has a majority of the cells containing a single enlarged nucleus plus one kinetoplast. There is also an enhanced population of anucleated cells, each containing a single kinetoplast known as the zoids (0N1K). The CRK3-depleted bloodstream form has an increased number of one nucleus-two kinetoplast cells (1N2K) and a small population containing aggregated multiple nuclei and multiple kinetoplasts. Apparently, these two forms have different mechanisms in cell cycle regulation. Although the procyclic form can be driven into cytokinesis and cell division by kinetoplast segregation without a completed mitosis, the bloodstream form cannot enter cytokinesis under the same condition. Instead, it keeps going through another G 1 phase and enters a new S phase resulting in an aggregate of multiple nuclei and multiple kinetoplasts in an undivided cell. The different leakiness in cell cycle regulation between two stagespecific forms of an organism provides an interesting and useful model for further understanding the evolution of cell cycle control among the eukaryotes.

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Section: From the Department Of Pharmaceutical Chemistry University supporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: From the Department Of Pharmaceutical Chemistry University mentioning

confidence: 99%

Section: From the Department Of Pharmaceutical Chemistry University mentioning

confidence: 99%

See 3 more Smart Citations

The Involvement of Two cdc2-related Kinases (CRKs) in Trypanosoma brucei Cell Cycle Regulation and the Distinctive Stage-specific Phenotypes Caused by CRK3 Depletion

Wang

2004

Journal of Biological Chemistry

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106

182

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Trypanosomatid Cell Division Kinases

Benz

Thomas

Hammarton

2013

Protein Phosphorylation in Parasites

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Advances have been made recently in understanding the order of events in the cell division cycles of Leishmania spp. and Trypanosoma cruzi, adding to previous knowledge of events in Trypanosoma brucei, and highlighting similarities and differences between these trypanosomatids. However, the present understanding of how the cell cycle is regulated by kinases still largely derives from analyses in T. brucei, since convenient genetic tools for analyzing the function of essential regulators -for example, inducible expression systems and/or RNA interferenceare still lacking in Leishmania and T. cruzi. While current understanding of the function of some kinases (e.g., some cyclin-dependent kinases, the NDR kinases, aurora, tousled-like and polo-like kinases) is now very good, many more remain to be characterized, as do details of the signal transduction pathways in which they operate. A number of protein kinases have, in recent years, been genetically -and in some cases also chemically -validated as potential novel drug targets for human African trypanosomiasis or leishmaniasis, although only a few, including CRK3: CYC6, CRK3:CYCA, the NDR kinases, PK50 and PK53 and polo-like kinase, have been subjected to high-throughput screening to identify small-molecule inhibitors. However, problems with these screens include a failure to identify potent inhibitors against the parasite enzyme in vitro, a lack of selectivity for the parasite enzyme over the equivalent human enzyme, or poor efficacy against the parasite. Thus, further chemical investigations will be required to generate new compounds with more ideal properties.

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Selection of Molecular Targets for Drug Development Against Trypanosomatids

Smirlis

Soares

2013

Subcellular Biochemistry

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Trypanosomatid parasites are a group of flagellated protozoa that includes the genera Leishmania and Trypanosoma, which are the causative agents of diseases (leishmaniases, sleeping sickness and Chagas disease) that cause considerable morbidity and mortality, affecting more than 27 million people worldwide. Today no effective vaccines for the prevention of these diseases exist, whereas current chemotherapy is ineffective, mainly due to toxic side effects of current drugs and to the emergence of drug resistance and lack of cost effectiveness. For these reasons, rational drug design and the search of good candidate drug targets is of prime importance. The search for drug targets requires a multidisciplinary approach. To this end, the completion of the genome project of many trypanosomatid species gives a vast amount of new information that can be exploited for the identification of good drug candidates with a prediction of "druggability" and divergence from mammalian host proteins. In addition, an important aspect in the search for good drug targets is the "target identification" and evaluation in a biological pathway, as well as the essentiality of the gene in the mammalian stage of the parasite, which is provided by basic research and genetic and proteomic approaches. In this chapter we will discuss how these bioinformatic tools and experimental evaluations can be integrated for the selection of candidate drug targets, and give examples of metabolic and signaling pathways in the parasitic protozoa that can be exploited for rational drug design.

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A PHO80-like Cyclin and a B-type Cyclin Control the Cell Cycle of the Procyclic Form of Trypanosoma brucei

Cited by 82 publications

References 31 publications

The Involvement of Two cdc2-related Kinases (CRKs) in Trypanosoma brucei Cell Cycle Regulation and the Distinctive Stage-specific Phenotypes Caused by CRK3 Depletion

The Involvement of Two cdc2-related Kinases (CRKs) in Trypanosoma brucei Cell Cycle Regulation and the Distinctive Stage-specific Phenotypes Caused by CRK3 Depletion

Trypanosomatid Cell Division Kinases

Selection of Molecular Targets for Drug Development Against Trypanosomatids

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