The Role of the MCTS1 and DENR Proteins in Regulating the Mechanisms Associated with Malignant Cell Transformation

Abstract

The mutations associated with malignant cell transformation are believed to disrupt the expression of a significant number of normal, non-mutant genes. The proteins encoded by these genes are involved in the regulation of many signaling pathways that are responsible for differentiation and proliferation, as well as sensitivity to apoptotic signals, growth factors, and cytokines. Abnormalities in the balance of signaling pathways can lead to the transformation of a normal cell, which results in tumor formation. Detection of the target genes and the proteins they encode and that are involved in the malignant transformation is one of the major evolutions in anti-cancer biomedicine. Currently, there is an accumulation of data that shed light on the role of the MCTS1 and DENR proteins in oncogenesis.

Keywords: MCTS1 and DENR proteins; apoptosis; cell cycle; malignant cell transformation; signaling pathways; translation initiation factors.

Figure 1

Domain structure of DENR, MCTS1, and eIF2D. DUF1947 – domain with unknown function; PUA – RNA-binding domain; SWIB/MDM2 – regions homologous to the SWIB protein involved in chromatin remodeling and the p53 inhibitor MDM2; SUI1 – protein region functionally similar to the initiation factor eIF1; WH (winged helix) – DNA-binding domain. MCTS1-homologous regions are highlighted in blue. DENR-homologous regions are highlighted in pink

Fig. 2

Schematic representation of the cell cycle. CDK – cyclin-dependent kinase; it is involved in cell cycle progression. Phosphorylation of the Rb (retinoblastoma protein) protein leads to transition through the G1/S stages. E2F – transcription factor; p16 (CDKN2A) – a CDK inhibitor; it impedes cell division while inhibiting G1/S transition; G1/S/G2 – interphase, M – mitosis

Fig. 3

Effect of MCTS1 on the pro-apoptotic protein p53 and its inhibitor p21. Formation of a complex between cyclin D1 and CDK4/6 and a complex between cyclin E and CDK2 regulates the transition through the G1 stage of the cell cycle

Fig. 4

Effect of MCTS1 on the PTEN/Src signaling. PTEN – an inhibitor of the PI3K/AKT/mTOR signaling pathway; Src – a protein kinase of the Src kinase family; RhoA – a transforming protein of the Ras family of GTPases

Fig. 5

Schematic illustration of the contribution of MCTS1 to EMT, tumor escape from immune surveillance, and activation of pro-inflammatory factors by tumor cells. EMT – epithelial-mesenchymal transition; Snail and Slug – transcription factors involved in EMT; EGFR – epidermal growth factor receptor; pro-inflammatory cytokines IL-6 – interleukin-6, MCP-1 – monocyte chemoattractant protein, and GM–CSF – granulocyte-macrophage colony-stimulating factor; M1 – classically activated macrophages providing the production of pro-inflammatory cytokines; M2 – macrophages responsible for anti-inflammatory response