ABCA1 p.Ala1407Thr
| Predicted by SNAP2: | C: N (57%), D: D (80%), E: D (75%), F: D (85%), G: D (66%), H: D (66%), I: D (95%), K: D (80%), L: D (53%), M: N (53%), N: D (66%), P: D (75%), Q: D (71%), R: D (59%), S: N (72%), T: D (85%), V: N (66%), W: D (95%), Y: D (80%), |
| Predicted by PROVEAN: | C: N, D: D, E: D, F: D, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: N, T: N, V: N, W: D, Y: D, |
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[hide] Anticancer Activity of the Cholesterol Exporter AB... Cell Rep. 2012 Sep 27;2(3):580-90. doi: 10.1016/j.celrep.2012.08.011. Epub 2012 Sep 13. Smith B, Land H
Anticancer Activity of the Cholesterol Exporter ABCA1 Gene.
Cell Rep. 2012 Sep 27;2(3):580-90. doi: 10.1016/j.celrep.2012.08.011. Epub 2012 Sep 13., [PMID:22981231]
Abstract [show]
The ABCA1 protein mediates the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I. Loss-of-function mutations in the ABCA1 gene induce Tangier disease and familial hypoalphalipoproteinemia, both cardiovascular conditions characterized by abnormally low levels of serum cholesterol, increased cholesterol in macrophages, and subsequent formation of vascular plaque. Increased intracellular cholesterol levels are also frequently found in cancer cells. Here, we demonstrate anticancer activity of ABCA1 efflux function, which is compromised following inhibition of ABCA1 gene expression by oncogenic mutations or cancer-specific ABCA1 loss-of-function mutations. In concert with elevated cholesterol synthesis found in cancer cells, ABCA1 deficiency allows for increased mitochondrial cholesterol, inhibits release of mitochondrial cell death-promoting molecules, and thus facilitates cancer cell survival, suggesting that elevated mitochondrial cholesterol is essential to the cancer phenotype.
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No. Sentence Comment
141 Two of the mutants (A1407T and A2109T) demonstrated a marked reduction in both cholesterol efflux and antitumor activity, while the other two mutants (E210D and D917Y) showed activity indistinguishable from the wild-type (wt) ABCA1 cDNA in both assays and in both human cancer cell lines used (Figure 4).
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ABCA1 p.Ala1407Thr 22981231:141:20
status: NEW142 Our data thus identify ABCA1 human colon cancer mutations A1407T and A2109T as loss-of-function mutations disabling both cholesterol efflux and antitumor activity.
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ABCA1 p.Ala1407Thr 22981231:142:58
status: NEW144 While expression of wt ABCA1 is strongly reduced following transplantation (see also Figure S1A for murine Abca1), expression of loss-of-function ABCA1 mutants A1407T and A2109T remains relatively unchanged, presumably because their antitumor activity is strongly diminished (Figure S4).
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ABCA1 p.Ala1407Thr 22981231:144:160
status: NEW