title: MAGE proteins regulate KRAB zinc finger transcription factors and KAP1 E3 ligase activity.
abstract: Expression of Melanoma AntiGen Encoding (MAGE) genes, particularly MAGE-A3, has been correlated with aggressive clinical course, the acquisition of resistance to chemotherapy and poor clinical outcomes of melanoma and other malignancies. MAGE proteins bind to KAP1, a gene repressor and ubiquitin E3 ligase which also binds KRAB domain containing zinc finger transcription factors (KZNFs), and MAGE expression may affect KZNF mediated gene regulation. To investigate mechanisms for these effects, we tested the hypothesis that differences in KRAB domain composition affect KZNF poly-ubiquitination and determine whether MAGE expression increases, decreases, or has no effect on KZNFs mediated gene repression. Using an integrated reporter gene responsive to repression by KRAB domain fusion proteins, we found that MAGE-A3 relieved KZNF mediated repression and induced KZNF poly-ubiquitination and degradation in association with expression of the A+B box KRAB domain. In contrast, MAGE-A3 enhanced KAP1 mediated repression of KZNFs expressing A or A+b box KRAB domains but caused no increase in poly-ubiquitination or degradation. MAGE-A3 has no significant impact on KZNFs with KRAB domains containing the Scan box motif. These data support our hypothesis by showing that the effects of MAGE-A3 on gene repression depend on the type of KZNF KRAB domain involved.
authors.affiliation: Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA. Electronic address: Txiao@dermatology.wisc.edu.
authors.forename: Tony Z
authors.initials: TZ
authors.lastname: Xiao
authors.affiliation: Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Yewseok
authors.initials: Y
authors.lastname: Suh
authors.affiliation: Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA; Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA. Electronic address: bjlongley@dermatology.wisc.edu.
authors.forename: B Jack
authors.initials: BJ
authors.lastname: Longley
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D003412:Cricetulus; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000076183:Tripartite Motif-Containing Protein 28; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000951:Antigens, Neoplasm; C072013:MAGEA3 protein, human; C405429:MAGEC2 protein, human; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C422407:ZNF350 protein, human; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D044767:Ubiquitin-Protein Ligases
keywords: KRAB; MAGE; Melanoma; ZNF
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