Posttranslational Modifications of Defined Embryonic Reprogramming Transcription Factors

Abstract

The generation of induced pluripotent stem cells (iPSCs) from somatic cells by expressing ectopic reprogramming transcriptional factors such as Oct3/4, Sox2, Klf4, c-Myc, and Nanog is one of the cutting-edge discoveries in stem cell and cancer research. This discovery has raised several safety issues regarding the use of iPSC technology for human disease research. Tumorigenesis is the major obstacle observed for iPSC-mediated transplantation therapy. Recently, a new method to generate human iPSCs either by a chemical method or by direct delivery of reprogramming factors has become a promising approach for future customized cell therapy of human disorders. These reprogramming transcriptional factors play critical roles in diverse cellular functions such as transactivation, cellular proliferation, differentiation, apoptosis, and tumorigenesis. Posttranslational modifications (PTMs) (phosphorylation, ubiquitination, acetylation, sumoylation, and so on) of these proteins act as a regulatory signal to control protein activity, expression, and stability in a wide variety of cellular processes. We attempt to summarize the accumulated evidence to address the role of PTMs of Oct3/4, Sox2, Klf4, c-Myc, and Nanog in regulating their biological functions. This review allows us to understand the importance of PTMs and their application in developing an efficient and safe reprogramming method without cancer development for cell therapy. Finally, we discuss the importance of PTMs of reprogramming factors in tumor pathogenesis.

An oncofetal and developmental perspective on testicular germ cell cancer

“…This is of interest, especially as specific iPS reprogramming protocols have been shown to induce GCC like tumors [199]. The parallel between GCCs (teratomas) and potential complications of stem cell therapy also illustrates this point [199][200][201]. OCT3/4, SOX2 and NANOG -together with a number of other factors -work in close harmony in regulating pluripotency.…”

“…They bind to a large numbers of promoter regions, including their own [202,203]. Apart from this complex crossover in auto-regulation of transcription they are all subjected to stringent post-translational control [201,204,205]. Key regulators of the pluripotency will be discussed in the context of TGCC in the following sections.…”

Regulation of pluripotency and differentiation by deubiquitinating enzymes

“…2,3 However, in addition to transcription-mediated regulation of ESC fate, recent studies have indicated that transcription-independent mechanisms also exist for controlling ESC fate. However, little information has been obtained regarding the role of posttranscriptional modifications (PTMs) in ESC maintenance and differentiation.…”

Future Application of Deubiquitylating Enzymes for Rapid and Efficient Cellular Reprogramming

“…ESCs can differentiate into three embryonic germ layers a) ectoderm -nerve and skin, b) mesoderm -bone, muscle, and blood c) endoderm -lung tissues and gut During cell division, each stem cell can either remain as stem cell or differentiate into a particular cell type. Several reports indicate the role of transcriptional factors such as c-Myc, Sox2, Oct4, Klf4, Lin28 and Nanog, in controlling the regulation of cellular reprogramming, stem cell pluripotency and differentiation [1,2]. In addition, post-translational modifications (PTMs) play a central part in directing multiple cellular processes through protein regulation.…”

“…PTMs such as sumoylation and phosphorylation are involved in the regulation of pluripotency-related transcriptional pathways [1,2]. PTMs also include the key regulatory cellular mechanism of ubiquitylation, which reverses upon deubiquitylation by DUBs.…”