title: Dimeric but not monomeric α-lactalbumin potentiates apoptosis by up regulation of ATF3 and reduction of histone deacetylase activity in primary and immortalised cells.
abstract: α-lactalbumin is a protein of dual function found in milk of most mammals. α-lactalbumin binds β-1,4-galactosyltransferase to form the regulatory subunit for lactose synthesis and has also been shown to cause cell death. This study shows, for the first time, that α-lactalbumin isolated in a rare 28kDa dimeric form induces cell death, while 14kDa monomeric α-lactalbumin is inactive. In contrast to the casein derived and chemically induced α-lactalbumin variants, MAL and HAMLET/BAMLET, the effects of 28kDa α-lactalbumin are calcium independent and, unlike MAL and HAMLET, 28kDa α-lactalbumin dimer causes cell death of primary mammary cells and a variety of immortalised cell lines, which are committed to cell death pathways within 1-4h of exposure. Microarray analysis confirmed that cell death was the result of an apoptotic response. Functional assays determined that the mechanism by which 28kDa α-lactalbumin kills cells involved inhibition of histone deacetylase activity mediated by NF-kB. We also show that 28kDa α-lactalbumin occurs naturally in the milk of cows, goats and sheep, is low in concentration during mid-lactation, but accumulates during milk stasis, consistent with a role in involution.
authors.affiliation: Institute for Frontier Materials, Deakin University, Geelong, VIC 3214, Australia. Electronic address: Julie.sharp@deakin.edu.au.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Sharp
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, VIC 3010, Australia.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Brennan
authors.affiliation: Monash Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia.
authors.forename: Galina
authors.initials: G
authors.lastname: Polekhina
authors.affiliation: Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC 3065, Australia.
authors.forename: David B
authors.initials: DB
authors.lastname: Ascher
authors.affiliation: Division of Bioinformatics, Walter and Eliza Hall Medical Research Institute, Melbourne 3000, Australia.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lefevre
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Nicholas
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002417:Cattle; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002850:Chromatography, Gel; D006041:Goats; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007768:Lactalbumin / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008970:Molecular Weight; D016328:NF-kappa B / Q000378:metabolism; D055503:Protein Multimerization; D012756:Sheep; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D051700:Activating Transcription Factor 3; D016328:NF-kappa B; D007768:Lactalbumin; D006655:Histone Deacetylases
keywords: Alpha-lactalbumin; Apoptosis; Cell death; Histone deacetylase inhibition; Involution, NF-κB