A P MacLaren's research while affiliated with Western General Hospital and other places

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Publications (1)

Figure 1: Annexin V time-course on KIM-2 cells. Cells were treated with MG132 over a 24 h period. Samples were harvested and an Annexin V assay performed. The results shown are the mean of three experiments±S.E.M., and are expressed as the percentage of Annexin V positive cells
Table 1 Effect of a range of protease inhibitors on KIM-2 mammary epithelial cells
Table 2 Induction of cell cycle arrest following proteasome inhibition in KIM-2 cells
Figure 3: Apoptosis analysis in a proliferating cell population. KIM-2 cells were passaged and treated with either DMSO, or serum and growth factor deprived, or cultured in the presence of 5 M MG132, at 4, 24, 48, 72, and 120 h after passaging. Cells were treated for a further 24 h and an Annexin V assay performed. Results are shown as the percentage of Annexin V positive cells, as the mean of three experiments±S.E.M. Cells were confluent at the 72 h stage. (b) Apoptosis induction as a consequence of proteasome inhibition following cell cycle synchronisation in KIM-2 cells. KIM-2 cells were passaged and allowed to grow for 24 h. Cells were subsequently blocked in G1/S-phase or at the G2/M boundary with Hydroxyurea (1 mM) or Nocodazole (50 ng/ml) respectively for 24 h (approximate cell division time). Following synchronisation cells were washed to remove the blocking drugs and then treated with either maintenance media (MM) or MM supplemented with 5 M MG132 over a 24 h period. Cells were harvested and an Annexin V assay performed. Results shown are expressed as the percentage of Annexin V positive cells. The data is the mean of three experiments±S.E.M. (c) Effect of proteasome inhibition on differentiated KIM-2 cells. KIM-2 cells differentiated for 12 days in the presence of prolactin and dexamethasone were treated with either 3% FCS or 5 M MG132 for 24 h. Cells were harvested and stained with annexin V. Results are expressed as the mean of three experiments±S.E.M.
Table 3 Induction of a G2/Mitosis arrest in ES cells by proteasome inhibition

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P53-dependent apoptosis induced by proteasome inhibition in mammary epithelial cells
  • Article
  • Full-text available

April 2001

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94 Reads

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83 Citations

Cell Death and Differentiation

A P MacLaren

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R S Chapman

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AH Wyllie

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We have examined the effects of inhibition of the 26S proteasome in a murine mammary cell line, KIM-2 cells using the peptide aldehyde inhibitor MG132. These studies have demonstrated a clear requirement for proteasome function in cell viability. Induction of apoptosis was observed following MG132 treatment in KIM-2 cells and this death was shown to be dependent on the cell actively traversing the cell cycle. KIM-2 cells were generated using a temperature sensitive T-antigen (Tag) and studies at the permissive temperature (33 degrees C) have shown that a Tag binding protein was essential for this apoptotic response. Studies in two additional cell lines, HC11, which is a mammary epithelial cell line carrying mutant p53 alleles and p53 null ES cells suggest that p53 is actively required for the apoptosis induced as a consequence of proteasome inhibition. These results suggest a pivotal role for the 26S proteasome degradation pathway in progression through the cell cycle in proliferating cells.

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Citations (1)

... BTZ (BTZ), a proteasome inhibitor, has shown beneficial effects in terms of survival improvement, tumor apoptosis, growth inhibition, and the suppression of angiogenesis and metastasis in preclinical in vivo studies. By suppressing the proteasome, BTZ stabilizes cyclin-dependent kinase inhibitors (p21 and p27), tumor suppressor p53, and proapoptotic proteins (Bid and Bax), thereby hindering cell cycle progression and inducing apoptosis [16][17][18][19][20]. Interestingly, the sensitivity to BTZ-induced apoptosis and chemosensitization appears to be cell-type dependent, with varying degrees of response observed with the p53 status [21][22][23][24][25]. ...

Reference:

Bortezomib exerts its anti-cancer activity through the regulation of Skp2/p53 axis in non-melanoma skin cancer cells and C. elegans
P53-dependent apoptosis induced by proteasome inhibition in mammary epithelial cells

Cell Death and Differentiation

A P MacLaren

·

R S Chapman

·

AH Wyllie

·