Alternative Variants of Pax4 Human Transcription Factor: Comparative Transcriptional Activity
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CULAR CELL BIOLOGY UDC 577.214
Alternative Variants of Pax4 Human Transcription Factor: Comparative Transcriptional Activity A. I. Melnikovaa, b, T. S. Krasnovaa, N. A. Zubkovac, A. N. Tiulpakovc, and P. M. Rubtsova, * a
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia Institute of Physics and Technology (State University), Dolgoprudny, Moscow oblast, 141701 Russia c Endocrinology Research Centre, Moscow, 117036 Russia *e-mail: [email protected]
bMoscow
Received April 21, 2020; revised April 21, 2020; accepted April 27, 2020
Abstract—MODY is a group of genetically and clinically heterogeneous forms of diabetes characterized by autosomal dominant inheritance and is subdivided in 13 subtypes dependent on the gene involved. The subtype MODY9 is a very rare form caused by mutations in the gene encoding the PAX4 transcription factor which is engaged in differentiation of pancreatic beta-cells. PAX4 contains two DNA-binding domains—Paired and Homeo. Expression of the human PAX4 gene is tissue-specific. The alternatively spliced mRNA variants encode for protein isoforms which differ within their N- and C-terminal regions. In this study, the transcriptional activities of the human PAX4 variants, both known and new ones, were determined. The full-length PAX4 containing intact DNA-binding domains was found to have maximal activity in transient expression system of the firefly luciferase reporter gene under control of the insulin promoter in HEK293 cells. The transcriptional activity is significantly reduced in the variants lacking eight N-terminal amino acid residues and/or variants whose Homeo domain is truncated from the C-terminus. Similar data were obtained with the glucagon promoter reporter system. The aberrant PAX4 variants were shown to retain stability and nuclear localization. Keywords: transcription factors, PAX4, monogenic diabetes MODY, MODY9, transcriptional activity, insulin gene promoter, glucagon gene promoter DOI: 10.1134/S0026893320050076
INTRODUCTION The PAX4 transcription factor plays important roles in organogenesis of the pancreas during embryonic development, these are, regulation of proliferation, migration of precursor cells and coordination of their differentiation programs, and resistance of insulin-producing cells to stress factors. In murine pancreatic α- and β-cell lines, PAX4 is bound to promoter regulatory elements of the main islet hormones: glucagon [1, 2], grehlin [3], and insulin [4]. Mutations in the human PAX4 gene are found in patients suffering from MODY9, one of the forms of MODY monogenic diabetes (Maturity Onset Diabetes of Young) [5, 6]. In the mature pancreas, PAX4 participates in adaptation to adverse factors. PAX4 includes two DNA-binding domains, Paired and Homeo, located in the N-terminal and central regions, respectively [7]. The important role of DNA-binding domains in PAX4 functioning is confirmed by the fact that the majority of missense mutations found in patients with different forms of diabetes substitute amino acids locat
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