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Transcription Factors (TFs) are proteins containing DNA-binding domains (DBDs), which attach to specific sequences of DNA adjacent to the genes that they regulate. By binding to the DNA they help initiate a program of increased or decreased gene transcription and are therefore essential for many important cellular processes (1, 2). Transcription factors are one of the groups of proteins that read and interpret the genetic "blueprint" in the DNA. TFs constitute the largest family of proteins in the human genome and are critical to making sure that the right genes are expressed in the right cell at the right time and in the right amount, responding to the changing requirements of the organism (3). Understanding the interplay between signaling cascades and transcription factors promises to advance our ability to combat disease and to reprogram cell fates (4, 5).
Stem Cell Transcription Factors.
In 2006, Shinya Yamanaka's team at Kyoto University, reported that normal cells (i.e. somatic cells that are already differentiated) can be reprogrammed back into stem cells by insertion of 4 ‘master’ transcription factors (6, 7).
These 4 transcription factors used in this study (Yamanaka Factors) are Oct4, KLF4, Sox2 and cMyc, and the cells created by their addition are termed induced Pluripotent Stem Cells (iPSC’s).
Subsequent research has shown that Yamanaka Factors can be introduced with mRNA (8), retrovirus carriers (9), introduction of Yamanaka Factor proteins themselves (10, 11), or mimicked by small molecules (12) to create iPSC’s.
Other transcription factors been found to be connected with this group of ‘master proteins’ (e.g. Lin28, Nanog, Sall2, and Olig2) (13, 14) and reprogramming can be influenced by manipulation of other proteins, e.g. p53 (15).
The medical possibilities that Stem Cell research has opened up has created an intense interest in all areas of research associated with iPSCs, e.g. signaling pathways upstream of Yamanaka factors (16-18), connection of such factors to disease conditions such as Carcinogenesis (19) and searches for drug compounds that might manipulate them (20).
While circumventing the major disputes associated with human ESCs, iPSCs offer the same advantages and, in addition, new perspectives for personalized medicine (21).
Cupid linked Yamanaka Factors.
The Cupid-Linked Yamanaka factors are the full length human proteins attached N-terminally to Cupid.
Oct4 (also termed Oct3/4 and Pou5f1) is one of a family of Octamer-binding transcription factors and its expression in nonmalignant cells is restricted to the pluripotent cells in the embryo and the primordial germ cells (22-24).
Oct3/4 been described as the only Yamanaka factor that cannot be substituted in this process by other members of the same protein family in iPSC generation and it has emerged as a master regulator of the induction and maintenance of cellular pluripotency with crucial roles in the early stages of differentiation (25).
Interestingly Oct3/4 contains a short sequence within it, credited with some capability as a cell membrane permeability factor itself (26).
KLF4 is a member of the zinc-finger transcription proteins, referred to as Krüppel-like factors (KLFs), which exert control over cellular quiescence (cell cycle arrest), proliferation, differentiation, development and apoptosis (27-29)
Sox proteins (Sox stands for Sry-related HMG box) are developmental regulators containing a highly conserved High Mobility Group region that binds DNA. They play roles in the instruction of cell fate and maintenance of progenitor's identity during embryogenesis, tissue homeostasis and regeneration in adults particularly in the Central Nervous System (30, 31)
Sox2 forms a core network with partner factors, thereby functioning as a molecular switch and making it a key factor in pluripotency (32).
A cell-permeable form of Sox2 (stabilized with supplements), has been reported to allow functional delivery into somatic cells (33).
The cMyc transcription factor protein features a basic Helix-Loop-Helix domain, termed th Leucine Zipper, which interacts with DNA and is believed to regulate expression of 15% of all genes. cMyc is activated upon various mitogenic signals such as Wnt, Shh and EGF (via the MAPK/ERK pathway). By modifying the expression of its target genes, Myc activation results in numerous biological effects and has fundamental roles in development, proliferation, apoptosis, tumorigenesis and stem cell pluripotency (34-36).