Transcription factor PAX4: role in differentiation of insulin producing beta cells during pancreas development and association with diabetes

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Аннотация

PAX4 (Paired Box 4) is a transcription factor that is expressed mainly in the pancreas and plays a key role in the development of insulin-producing β-cells at the embryonic stage, and in mature cells it is the main regulator of their adaptation under pathological conditions. The importance of this factor for the proper functioning of the pancreatic islets was demonstrated by studying the relationship between mutations in the PAX4 gene and the development of diabetes mellitus. Overexpression of this factor in adult islets stimulates β-cell proliferation and resistance to apoptosis. Taken together, these data indicate that PAX4 may be a potential target in the development of new diabetes treatments aimed at reprogramming different cell types into insulin-producing cells and promoting their proliferation to replenish β-cell mass lost during disease progression. The development of such methods requires knowledge of the molecular mechanisms that control the expression of PAX4 and its target genes. This review summarizes data on the structure and expression of the human PAX4 gene. The interaction of different transcription factors during the differentiation of pancreatic cells and the formation of islets of Langerhans and the role of PAX4 in these processes are described. The relationship between mutations in the human PAX4 gene and the development of various forms of diabetes mellitus is examined. The final part of the review examines the prospects for reprogramming different types of cells into insulin-producing cells and influencing PAX4-regulated signaling pathways in the development of new approaches to the treatment of diabetes mellitus.

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Авторлар туралы

А. Melnikova

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; Moscow Institute of Physics and Technology (State University)

Email: rubtsov@eimb.ru
Ресей, Moscow; Dolgoprudny, Moscow Region

T. Krasnova

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: rubtsov@eimb.ru
Ресей, Moscow

P. Rubtsov

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Хат алмасуға жауапты Автор.
Email: rubtsov@eimb.ru
Ресей, Moscow

Әдебиет тізімі

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2. Fig. 1. Spatial structure of the PAX4 protein (alphafold.com).

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3. Fig. 2. Schematic representation of the PAX4 protein structure. The conserved N-terminal half of the protein contains DNA-binding domains, while the C-terminal region includes transactivation (TAD) and negative regulation (DNR) domains. Amino acid residues in PAX4 variants identified during gene sequencing in patients with different forms of diabetes are indicated. The length of the N-terminal sequence in alternative protein isoforms differs by eight residues, so the positions of amino acid substitutions in the two types of isoforms are indicated (e.g., R19/27W).

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4. Fig. 3. Schematic representation of the exon-intron structure of the PAX4 gene (a), alternative PAX4 mRNA isoforms (b), and N-terminal regions of the protein isoforms (c). P1, P2 are alternative gene promoters. Synthesis of the protein encoded by mRNA isoform 3 is initiated from an alternative AUG codon, therefore this protein is shortened from the N-terminus by eight amino acid residues compared to the proteins encoded by mRNA isoforms 1 and 2 (Uniprot database: O43316).

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