Abstract
Protein phosphatase 2A (PP2A) is a ubiquitously expressed Serine-Threonine phosphatase mediating 30–50% of protein phosphatase activity. PP2A functions as a heterotrimeric complex, with the B subunits directing target specificity to regulate the activity of many key pathways that control cellular phenotypes. PP2A-B56α has been shown to play a tumor suppressor role and to negatively control c-MYC stability and activity. Loss of B56α promotes cellular transformation, likely at least in part through its regulation of c-MYC. Here we report generation of a B56α hypomorph mouse with very low B56α expression that we used to study the physiologic activity of the PP2A-B56α phosphatase. The predominant phenotype we observed in mice with B56α deficiency in the whole body was spontaneous skin lesion formation with hyperproliferation of the epidermis, hair follicles and sebaceous glands. Increased levels of c-MYC phosphorylation on Serine62 and c-MYC activity were observed in the skin lesions of the B56αhm/hm mice. B56α deficiency was found to increase the number of skin stem cells, and consistent with this, papilloma initiation was accelerated in a carcinogenesis model. Further analysis of additional tissues revealed increased inflammation in spleen, liver, lung, and intestinal lymph nodes as well as in the skin lesions, resembling elevated extramedullary hematopoiesis phenotypes in the B56αhm/hm mice. We also observed an increase in the clonogenicity of bone marrow stem cells in B56αhm/hm mice. Overall, this model suggests that B56α is important for stem cells to maintain homeostasis and that B56α loss leading to increased activity of important oncogenes, including c-MYC, can result in aberrant cell growth and increased stem cells that can contribute to the initiation of malignancy.
Highlights
Protein Phosphatase 2A (PP2A) is a heterotrimeric Serine-Threonine protein phosphatase that is ubiquitously expressed in eukaryotic cells [1] and mediates 30–50% of cellular Serine/Threonine protein phosphatase activity [2]
PPP2R5A (B56α) deficient mice were generated by integration of a gene trap vector with a splice acceptor (SA) site followed by the lacZ-neo (BGEO) cassette (developed by Texas A&M Institute for Genomic Medicine (TIGM)) into the first intron of B56α (Fig 1A) [27]
In this study we report that B56α depletion in mice contributes to the formation of skin lesions that show hyperproliferation in the epidermis, hair follicles, and sebaceous glands
Summary
Protein Phosphatase 2A (PP2A) is a heterotrimeric Serine-Threonine protein phosphatase that is ubiquitously expressed in eukaryotic cells [1] and mediates 30–50% of cellular Serine/Threonine protein phosphatase activity [2]. 15 genes encode 26 B subunits of PP2A, which can potentially assemble more than 100 distinct PP2A complexes [3,4,5,6,7]. Many of these subunits have distinct spatial and temporal expression patterns, and details about the different complexes and their activities remain incompletely understood
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