Spindle proteins

Entry of animal cells into mitosis is based on the mitosis-promoting factor (MPF). MPF consists of CDK1 (cdc2) and cyclin B. The intracellular concentration of cyclin B increases constantly until mitosis starts, and then declines again rapidly (top left). MPF is initially inactive, because CDKl is phosphorylated and cyclin B is dephosphorylated (top center). The M phase is triggered when a protein phosphatase [1] dephosphorylates the CDK while cyclin B is phosphorylated by a kinase [2]. in its active form, MPF phosphorylates various proteins that have functions in mitosis—e.g., histone HI (see p. 238), components of the cytoskeleton such as the laminins in the nuclear membrane, transcription factors, mitotic spindle proteins, and various enzymes. 

It is known that pyrazolines and pyrazoles are an important class of pharmacophores [1,2,3,4, 5,6], Heterocycles containing these fragments are important targets in synthetic and medicinal chemistry since they are key moieties in numerous biologically active compounds possessing tranquilizing, muscle relaxant, psychoanaleptic, anticonvulsant and antidepressant activities [7, 8, 9,10,11,12], This includes kinesin spindle protein [12] and monoamine oxidase [13, 14] inhibitors as well as antimycobacterial [15, 16] and anti-inflammatory [17] agents. 

Zhang, Y., and Xu, W. (2008) Progress on kinesin spindle protein inhibitors as anticancer agents. Anticancer Agents Med. Chem. 8, 698-704. 

In all eukaryotes, three components participate in attaching chromosomes to microtubules the centromere, kinetochore and spindle proteins, and the cell-cycle machinery. The location of the centromere and hence that of the kinetochore Is directly controlled by a specific sequence of chromosomal DNA termed centromeric DNA (Chapter 10). Although the sequences of centromeric DNA and of DNA-binding proteins In the kinetochore are not well conserved through evolution, the cell-cycle proteins and many of the... 

The 3,4-dialkylated-4i/-l-oxa-2,4-diazine-5(6f/)-one ring features in a series of compounds such as 270 designed as inhibitors of kinesin spindle protein (KSP) that have potential in the treatment of proliferative diseases such as cancer, hyperplasias, restenosis, and cardiac hypertrophy <2004W02004091547>. 3,5-Disubstituted-5,6-dihydro-4/7-l-oxa-2,4-diazines such as 271 have been prepared for their use in the treatment of vascular diseases <2003W02003057664>. 

The relationships between mitotic mechanisms and certain very general problems in cell biology are now becoming clearer, if only in terms of the questions and not the answers. The major new area of contact is self-assembly, researches on assembly of viral and other proteins give a new view of many mitotic problems. In turn, given the in-vivo observations and experiments on mitosis available for correlation, future in-vitro studies of isolated chromosomes and spindle proteins promise a larger view of the functional role of reversible self-assembly. This and several other general problems may be clear from the earlier considerations, but a most basic one needs more explicit discussion. 

Ni(II) has a much higher affinity for proteins than for DNA (Ciccarelli and Wetterhahn 1985), which might help to explain its propensity to react with heterchromatin. Ni3S2 was also reported to interfere with spindle proteins, which could lead to aneuploidy (Swierenga and McLean 1984). Oxidized bases resulted when chromatin was exposed to Ni(II) alone, and it was suggested that some Ni(II)-protein complexes are able to generate free... 

There is evidence that the centres (poles) from which the spindle develops are C3rtoplasmic structures and that they divide in the cytoplasm either before mitosis is complete or very early in interphase. Further, it is during interphase that the proteins which will go to form the spindle and its fibres are synthesised. This must mean that a very considerable part of protein synthesis in meristem-atic cells must be concerned with the synthesis of the spindle proteins. 

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