[Transcription Factor Sp1 in the Expression of Genes Encoding Components of MAPK, JAK/STAT, and PI3K/Akt Signaling Pathways].

Sp1 is a transcription factor of the Sp/KLF family that binds to GC-rich motifs in regulatory regions of genes. Sp1 is involved in the regulation of cell proliferation, apoptosis and differentiation, and angiogenesis. A high level of SP1 expression, as well as its aberrant transcriptional activity due to post-translational modifications, is found in cells in oncological diseases, such as lung, breast, pancreatic, thyroid, gastric cancer, and glioma; congenital heart disease, as well as neurodegenerative disorders, including Huntington's and Parkinson's diseases. Binding of Sp1 to GC-rich motifs of the regulatory regions of the genes encoding components of the MAPK, p38, JAK/STAT, PI3K/Akt signaling pathways, is involved in the control of cell proliferation, differentiation, and death. In addition, kinases of these signaling pathways are able to change the transcriptional activity of Sp1 by phosphorylation of certain amino acid residues, which leads to a change in the efficiency of its binding to cofactors and DNA regulatory regions. This review presents data on the relationship between the Sp1 transcription factor and the activity of the MAPK, p38, JAK/STAT, and PI3K/Akt signaling pathways in normal tissues and in various pathologies, including malignant diseases.

[High Expression Level of SP1, CSF1R, and PAK1 Correlates with Sensitivity of Leukemia Cells to the Antibiotic Mithramycin].

Acute myeloid leukemia (AML) is a genetically heterogeneous group of oncological diseases of the hematopoietic system, which are extremely difficult to treat. The development of new targeted drugs (Hylteritinib, Venetoclax) significantly improved the survival of patients, but resistance, as well as cytotoxic anti-leukemia drugs, often occurs. The search for new molecular targets for the development of effective approaches for the treatment of AML is very urgent. In blast cells of patients with AML, mutations, chromosomal rearrangements, and increased expression of a number of non-mutant genes, including transcription factor genes, are detected. The transcription factor Sp 1 binds to GC-rich regions of regulatory regions of various genes and thus controls their expression. Sp1 targets include genes responsible for proliferation, cell cycle regulation, and differentiation. In many malignant diseases, a high level of Sp1 gene expression is associated with an unfavorable prognosis, therefore, Sp1 is considered as a promising therapeutic target for cancer. In this paper, we estimated the expression levels of Sp1 in various malignant tissues. Increased Sp1 expression was detected in samples obtained from patients with AML, acute lymphoblastic leukemia, Ewing sarcoma, ovarian and kidney cancer. It is also shown that Sp1 expression correlates with the expression of genes encoding cytokine receptors and growth factors (CSF1R and IL6R), intracellular kinases (CSK, SYK, PAK1, ILK, JAK2), and transcription factor LMO2. The correlation between expression levels of Sp1 and CSF1R, SYK, Jak2 and LMO2 is also characteristic of transplanted human leukemia cells. We measured expression levels of Sp1, CSF1R, ILK, PAK1 in the cells of three transplantable lines of human leukemia and found increased levels of expression of these genes in Kasumi-1 cells. In addition, we showed that Kasumi-1 cells are most sensitive to Mitramycin, a drug that displaces Sp1 from its targets with DNA. Our data indicate the need to identify AML cells that are most sensitive to inhibition of Sp1 activity in order to assess the possibility of suppressing its activity in vivo.