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Beta-sheet-specific...
Beta-sheet-specific interactions with heat shock proteins define a mechanism of delayed tumor cell death in response to HAMLET
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- Nadeem, Aftab (author)
- Lund University,Lunds universitet,Avdelningen för mikrobiologi, immunologi och glykobiologi - MIG,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Microbiology, Immunology and Glycobiology - MIG,Department of Laboratory Medicine,Faculty of Medicine
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- Ho, James C.S. (author)
- Lund University,Nanyang Technological University
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- Tran, Tuan Hiep (author)
- Lund University
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- Paul, Sanchari (author)
- Lund University,Lunds universitet,Cancerinfektion,Forskargrupper vid Lunds universitet,Cancer Infection,Lund University Research Groups
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- Granqvist, Victoria (author)
- Lund University,Lunds universitet,Tumörcellsbiologi,Forskargrupper vid Lunds universitet,Tumor Cell Biology,Lund University Research Groups
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- Despretz, Nadege (author)
- Lund University
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- Svanborg, Catharina (author)
- Lund University,Lunds universitet,Cancerinfektion,Forskargrupper vid Lunds universitet,Cancer Infection,Lund University Research Groups
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(creator_code:org_t)
- Elsevier BV, 2019
- 2019
- English.
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In: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836. ; 431:14, s. 2612-2627
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http://dx.doi.org/10...
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https://doi.org/10.1...
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Abstract
Subject headings
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- As chaperones, heat shock proteins (HSPs)protect host cells against misfolded proteins that constitute a by-product of protein synthesis. Certain HSPs are also expressed on the surface of tumor cells, possibly to scavenge extracellular unfolded protein ligands and prevent them from becoming cytotoxic. HAMLET—a complex of partially unfolded alpha-lactalbumin and oleic acid—is relying on its N-terminal alpha-helical domain to perturb tumor cell membranes, and the cells die as a consequence of this interaction. Here we show that in parallel, cell surface HSPs bind the beta-sheet domain of alpha-lactalbumin and activate a temporarily protective loop, involving vesicular uptake and lysosomal accumulation. Later, HAMLET destroys lysosomal membrane integrity, and HAMLET release kills the remaining tumor cells. HSPs were identified as HAMLET targets in a proteomic screen and Hsp70-specific antibodies or shRNAs inhibited HAMLET uptake by tumor cells, which showed increased Hsp70 surface expression compared to differentiated cells. The results suggest that HAMLET engages tumor cells by two parallel recognition mechanisms, defined by alpha-helical- or beta-sheet domains of alpha-lactalbumin and resulting in an immediate death response, or a delay due to transient accumulation of the complex in the lysosomes. This dual response pattern was conserved among tumor cells but not seen in normal, differentiated cells. By two different mechanisms, HAMLET thus achieves a remarkably efficient elimination of tumor cells.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- beta peptide
- lysosome
- scavenger
- tumoricidal activity
- unfolded protein
Publication and Content Type
- art (subject category)
- ref (subject category)
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