Cell cycle and pluripotency: Convergence on octamer‑binding transcription factor 4 (Review)

Abstract

Embryonic stem cells (ESCs) have unlimited expansion potential and the ability to differentiate into all somatic cell types for regenerative medicine and disease model studies. Octamer‑binding transcription factor 4 (OCT4), encoded by the POU domain, class 5, transcription factor 1 gene, is a transcription factor vital for maintaining ESC pluripotency and somatic reprogramming. Many studies have established that the cell cycle of ESCs is featured with an abbreviated G1 phase and a prolonged S phase. Changes in cell cycle dynamics are intimately associated with the state of ESC pluripotency, and manipulating cell‑cycle regulators could enable a controlled differentiation of ESCs. The present review focused primarily on the emerging roles of OCT4 in coordinating the cell cycle progression, the maintenance of pluripotency and the glycolytic metabolism in ESCs.

Figure 1.

An overview of the roles of OCT4 in coordinating the G1/S transition and the maintenance of pluripotency. OCT4 promotes the phosphorylation of hypo-phosphorylated RB (a prerequisite for the R-point transition) by downregulating PP1 and upregulating CDK4/6-Cyclin D in early and mid G1 phase. At this point, phosphorylated RB still binds to E2Fs and blocks their transcription-activating domains, leading to suppressed expression of several cell-cycle promoting genes, including OCT4. OCT4 can further promote RB hyperphosphorylation by upregulating CDK2-Cyclin E complex, which leads to the E2F release, the R-point transition, and the entry into the S phase. CDK2 can also phosphorylate SOX2 to enhance reprogramming efficiency. Black arrows indicate positive regulation, while red bar-headed lines indicate negative regulation. PP1, protein phosphatase 1; CDK, cyclin-dependent kinase; FOXM1, forkhead box protein M1; RB, retinoblastoma; E2F, E2F transcription factor 1; OCT4, octamer-binding transcription factor 4; p, phosphorylated.

Figure 2.

An overview of the roles of OCT4 in coordinating the G2/M transition and the maintenance of pluripotency. At the G2/M phase, via a non-transcriptional mechanism, OCT4 can inhibit the activation of CDK1 and lead to a prolonged G2 phase, allowing for subsequent checking of genome integrity and reducing chromosomal mis-segregation. Reciprocally, CDK1 can enhance the binding of OCT4 to the CDX2 promoter and suppress its transcription, contributing to the maintenance of ESC pluripotency. Black arrows indicate positive regulation, while red bar-headed lines indicate negative regulation. CDX2, homeobox protein CDX2; CDC25, cell cycle division 25; miR, microRNA; CDK1, cyclin-dependent kinase 1; GADD45, DNA-damage-inducible protein 45; SOX2, SRY-box 2; OCT4, octamer-binding transcription factor 4.