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Fig. 6 | Molecular Cancer

Fig. 6

From: C-Src confers resistance to mitotic stress through inhibition DMAP1/Bub3 complex formation in pancreatic cancer

Fig. 6

DMAP1 Y246 phosphorylation is required for tumourigenesis. a and b, A total of 5 × 106 SW1990 cells with Bub3 or DMAP1 depletion and reconstituted expression of the WT rBub3/WT rDMAP1, WT rBub3/rDMAP1 Y246F or rBub3 S211A/rDMAP1 Y246F were subcutaneously injected into the athymic nude mice. Paclitaxel (5 mg/kg) was injected intraperitoneally every two days once the volume of tumours reached 200 mm3. Data represent the mean ± s.e.m. (n = 8). *represents p < 0.05 and **represents p < 0.01 between indicated groups. Representative tumour xenografts were shown (a). Tumour volumes and weight were measured. In the measurement of tumour volumes, length (a) and width (b) and calculated using the following equation: V = ab2/2. Data represent the means ± s.e.m. (n = 8, right panel) (b). c and d Immunoblotting analyses (c) and Immunohistochemical staining (d) with anti-DMAP1 pY246 was performed on human pancreas tumour specimens. Representative photos were shown. For immunoblotting analyses, the numbers underneath the blotting bands represent the normalized density quantified by using densitometry using Image J 2 × software. e, The survival times for 90 patients with low (0–2 staining scores, blue curve) versus high (2.1–5 staining scores, red curve) DMAP1 Tyr246 phosphorylation (low, 29 patients; high, 61 patients) (upper right) were compared. The Kaplan-Meier method and log-rank tests indicating the significance level of the association of DMAP1 Tyr246 phosphorylation (p = 0.014) with patient survival. The table (lower) shows the cox-multivariate analysis after adjustment for patient sex and age, indicating the significance level of the association of DMAP1 Tyr246 phosphorylation (p = 0.0247, HR = 1.942) with patient survival. f, The schematic diagram showing the regulatory role of Bub3/DMAP1 complex in DNA methylation upon mitotic stress in normal pancreatic epithelial cells and pancreatic cancer cells. Mitotic arrest induces p38 activation, which phosphorylates Bub3 at Ser 211 and promotes its interaction with DMAP1/DNMT1. TAp73 recruits Bub3/DMAP1 complex to promoter regions of its-targeted genes, where DMAP1/DNMT1 mediates DNA methylation and blocks expression of genes responsible for anti-apoptosis. c-Src can phosphorylate DMAP1 at Tyr246, which disrupts Bub3/DMAP1 complex formation. In normal cells with limited c-Src activity, p38/Bub3/DMAP1 signaling is readily activated under mitotic arrest; in turn, cells are prone to apoptosis (left part). In cancer cells, hyperactive c-Src leads to DMAP1 tyr246 phosphorylation and inhibits mitotic arrest-induced cell apoptosis mediated by p38/Bub3/DMAP1 signaling (right part)

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