Macrophage Differentiation and Growth Inhibition by METS
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Macrophage Differentiation and Growth Inhibition by METS
Cell differentiation begins only when the cell proliferation mechanism is seized, and the macrophage differentiation system is a good example, as the macrophages start to differentiate only when they stop proliferating. Molecular mechanisms which act coordinately in order to regulate cell proliferation and differentiation are vital in development. Induction of Ets (v-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog) repressor that is METS (Mitogenic Ets Transcriptional Suppressor) leads to terminal differentiation and cell cycle arrest (Ref.1). Macrophages are models, which provide evidence that METS blocks HRas (v-Ha-Ras Harvey Rat Sarcoma Viral Oncogene Homolog)-dependent proliferation without inhibiting HRas-dependent expression of cell type-specific genes by selectively replacing Ets activators on the promoters of cell cycle control genes. Anti-proliferative effects of METS require its interaction with DP103 (DEAD-Box Protein-DP103) that assembles a novel co-repressor complex. The transcriptional repression involving METS with DP103 is selective and does not involve all Ets regulated genes. While cell cycle genes are repressed by METS, other gene activated by Ets factors such as those involved in differentiation are not repressed by METS. The transcriptional repression by METS also involved members of the Rb (Retinoblastoma) family of tumor suppressors, such as Rb, p107 and p130. METS and DP103 interaction also suppress functioning of the cell cycle gene, E2F4 (E2F Transcription Factor-4), proteins like HDACs (Histone Deacetylases), NCORs (Nuclear Receptor Co-Repressors) and Sin3s (Sin3 Homolog Transcriptional Regulators). METS is assumed to be regulated by serine phosphorylation but experimental data showing this regulation is still lacking. (Ref.2 & 3).

HRas signaling initiated by MCSF (Macrophage Colony Stimulating Factor) through CSF1R (Colony-Stimulating Factor-1 Receptor) leads to transcriptional activation of a large set of target genes by a mechanism that depends on cooperative interactions between Ets factors (Ets1 and Ets2) and members of the Activator Protein-1 family of transcription factors (c-Jun (v-Jun Avian Sarcoma Virus-17 Oncogene) and c-Fos (Cellular Oncogene Fos)). Induction of the Ets repressor METS during macrophage differentiation contributes to terminal cell cycle arrest by repressing the transcription of cell cycle control genes that include c-Myc (v-Myc Avian Myelocytomatosis Viral Oncogene Homolog), c-Myb (v-Myb Avian Myeloblastosis Viral Oncogene Homolog) and CDC2 (Cell Division Cycle-2) (Ref.2). While METS exhibits an overlapping DNA binding specificity with Ets2 and other Ets activators, it does not inhibit transcription of macrophage-specific genes that are activated by Activator Protein-1/ Ets ternary complexes. METS selectively represses Ets target genes involved in Ras (a membrane associated Guanine nucleotide-binding protein)-dependent proliferation while sparing genes that are targets of Ras-dependent differentiation (Ref.3).