A main player in the latter pathway is a GTPase Ran, whose activator, RCC1, is concentrated on the chromosomes. Thereby, Ran locally activates several downstream proteins required for spindle assembly, such as the microtubulestabilising protein HURP and the crosslinker kinesin-14. TPX2 is one of the best-characterised targets of Ran. This conserved microtubule-associated protein was originally identified as a protein required for targeting kinesin-12 to the spindle pole in Xenopus egg extracts. Subsequent functional studies have established that TPX2 is essential for spindle assembly, in particular for spindle pole organisation in a variety of cell types. TPX2 is imported into the nucleus by importin binding during interphase and is subsequently activated by the removal of importin by RanGTP following nuclear envelope breakdown . Several conserved domains have been identified in TPX2, including regions responsible for nuclear localisation, activation of the Aurora A kinase, microtubule nucleation and stabilisation, and kinesin-5 binding. The mechanism of Aurora A activation has been elucidated at the atomic level, and structure-function studies have clarified the importance of this domain in spindle size control and suggested its role in spindle assembly itself . Although the microtubule nucleation activity has been shown in vitro, the physiological significance of this activity has been controversial; lack of microtubule generation in the absence of TPX2 in cells has been suggested to be due to stabilisation defects rather than nucleation problems. TPX2 is most concentrated at spindle poles partly due to motor-dependent transport, but it is also localised all along the spindle microtubules. Although the organisation of these domains is generally conserved among multicellular organisms, there are 2 exceptions. In Caenorhabditis elegans, the TPX2-like protein appears to be missing all the conserved domains other than that responsible for Aurora A activation. Another, perhaps more mysterious issue is that homologous proteins to TPX2 have not been found in the genome of Drosophila melanogaster, one of the most popularly used model animal species for cell division research, although HURP and kinesin-14, 2 other Ran targets have been identified as the nuclear and spindle proteins. The Drosophila Ssp1/Mei-38 gene was identified in 2 independent studies. In a genome-wide RNAi screen for spindle morphology, knockdown of this gene elevated the percentage of spindles with slightly abnormal morphology, such as shorter, monastral bipolar or monopolar spindles. On the other hand, genetic screening by Baker and Carpenter identified an allele of mei-38 for elevated levels of X chromosome nondisjunction in female flies, and GDC-0879 recent cloning by Wu et al. revealed that Mei-38 is identical to Ssp1. The null mutant exhibits defects in meiotic spindle morphology in female flies. However, although slight spindle organization defects are seen in mitotic cells in the larval brain, the mutant is completely viable with no noticeable defects.

Suggests that the prognostic value of Ki-67 on survival was greater in the tumors located in the nodes than that in the primary lesion. Potential limitations of this manuscript include the variation in quantitating Ki-67 staining by immunohistochemistry between the two pathologists. Despite the potential variability of the quantitation of Ki-67 IHC staining, statistical analysis indicated that Ki-67 status was an independent prognostic factor for overall survival and MFS in patients with 1–3 positive nodes. To date, several studies have also indicated that Ki-67 expression may be a marker for predicting the sensitivity of chemotherapy, and that Ki-67 expression before and after neoadjuvant therapy may be employed for predict prognosis. Currently, differences in the Ki-67-detection methods and cutoff points likely contribute to the varied conclusions on the prognostic value of Ki-67 expression in breast cancer patients. Thus, prospective studies with large sample size, standardized methodology and specialized personnel for Ki-67 detection in a single center or international guidelines are warranted. Taken together, Ki-67 expression together with clinical factors may favorably predict the prognosis of breast cancer patients with positive axillary lymph nodes, especially for those with 1–3 positive axillary lymph nodes, which may provide reference for prescribing individualized therapy of breast cancer. Ubiquitination is a key process for the regulation of proteins in the cell and failure of ubiquitin pathways in the brain is linked to neuropathological states such as Parkinson’s disease . The targeting of proteins for ubiquitination relies on enzymes known as E3 ubiquitin ligases and their adaptor proteins; together they identify proteins for the addition of ubiquitin resulting in target protein degradation or alternatively, protein trafficking. Ndfip1 is an adaptor protein for the Nedd4 family of ubiquitin ligases and has been found to be upregulated in neurons after brain injury, including head trauma, stroke and metal toxicity. The upregulation of Ndfip1 is associated with binding and ubiquitination of a number of different protein substrates. One of these is the divalent metal transporter DMT1, which is targeted for ubiquitination and degradation in both the brain and liver in response to rising levels of transition metals. Specifically, Fe2+ and Co2+ can both stimulate increased Ndfip1 levels within primary human neurons in culture. This upregulation leads to a complex forming between Ndfip1, DMT1 and the ubiquitin ligase Nedd4- 2, and results in the ubiquitination of DMT1 followed by its degradation. The removal of DMT1 protects neurons from metal MLN4924 toxicity by limiting metal ion entry. The present study was motivated by studies that report the involvement of DMT1 in the pathogenesis of PD. PD is characterised by the degeneration of dopaminergic neurons in the substantia nigra and the accumulation of cytoplasmic Lewy body inclusions in these neurons. However, PD is also directly associated with the intracellular accumulation of iron, particularly in the substantia nigra.