Cupid Transcription Factors

Transcription Factors

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).



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3. Genesis of Chromatin and Transcription Dynamics in the Origin of Species. Koster MJ, Snel B, Timmers HT. Cell. 2015 May 7;161(4):724-736. doi: 10.1016/j.cell.2015.04.033. Review. PMID: 25957681

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6. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Takahashi K, Yamanaka S. Cell. 2006 Aug 25;126(4):663-76. Epub 2006 Aug 10. PMID: 16904174 Free Article

7. Patient-specific pluripotent stem cells become even more accessible. Yamanaka S. Cell Stem Cell. 2010 Jul 2;7(1):1-2. doi: 10.1016/j.stem.2010.06.009. PMID: 20621038 Free Article

8. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, Ebina W, Mandal PK, Smith ZD, Meissner A, Daley GQ, Brack AS, Collins JJ, Cowan C, Schlaeger TM, Rossi DJ. Cell Stem Cell. 2010 Nov 5;7(5):618-30. doi: 10.1016/j.stem.2010.08.012. Epub 2010 Sep 30. PMID: 20888316 Free PMC Article

9. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Meissner A, Wernig M, Jaenisch R. Nat Biotechnol. 2007 Oct;25(10):1177-81. Epub 2007 Aug 27. PMID: 17724450

10. Partial somatic to stem cell transformations induced by cell-permeable reprogramming factors. Lim J, Kim J, Kang J, Jo D. Sci Rep. 2014 Mar 12;4:4361. doi: 10.1038/srep04361. PMID: 24618595 Free PMC Article

11. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS, Ko S, Yang E, Cha KY, Lanza R, Kim KS. Cell Stem Cell. 2009 Jun 5;4(6):472-6. doi: 10.1016/j.stem.2009.05.005. Epub 2009 May 28. No abstract available. PMID: 19481515 Free PMC Article

12. Non-viral methods for generating integration-free, induced pluripotent stem cells. Deng XY, Wang H, Wang T, Fang XT, Zou LL, Li ZY, Liu CB. Curr Stem Cell Res Ther. 2015;10(2):153-8. PMID: 25248676

13. Induced pluripotent stem cell lines derived from human somatic cells. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. Science. 2007 Dec 21;318(5858):1917-20. Epub 2007 Nov 20. PMID: 18029452 Free Article

14. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Suvà ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, Riggi N, Chi AS, Cahill DP, Nahed BV, Curry WT, Martuza RL, Rivera MN, Rossetti N, Kasif S, Beik S, Kadri S, Tirosh I, Wortman I, Shalek AK, Rozenblatt-Rosen O, Regev A, Louis DN, Bernstein BE. Cell. 2014 Apr 24;157(3):580-94. doi: 10.1016/j.cell.2014.02.030. Epub 2014 Apr 10. PMID: 24726434 Free PMC Article

15. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Hong H, Takahashi K, Ichisaka T, Aoi T, Kanagawa O, Nakagawa M, Okita K, Yamanaka S. Nature. 2009 Aug 27;460(7259):1132-5. doi: 10.1038/nature08235. Epub 2009 Aug 9. PMID: 19668191 Free PMC Article

16. Cell signalling pathways underlying induced pluripotent stem cell reprogramming. Hawkins K, Joy S, McKay T. World J Stem Cells. 2014 Nov 26;6(5):620-8. doi: 10.4252/wjsc.v6.i5.620. Review. PMID: 25426259 Free PMC Article

17. Molecular mechanisms of induced pluripotency. Kulcenty K, Wróblewska J, Mazurek S, Liszewska E, Jaworski J. Contemp Oncol (Pozn). 2015;19(1A):A22-9. doi: 10.5114/wo.2014.47134. Review. PMID: 25691818 Free PMC Article

18. Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells. Carey BW, Markoulaki S, Hanna JH, Faddah DA, Buganim Y, Kim J, Ganz K, Steine EJ, Cassady JP, Creyghton MP, Welstead GG, Gao Q, Jaenisch R. Cell Stem Cell. 2011 Dec 2;9(6):588-98. doi: 10.1016/j.stem.2011.11.003. PMID: 22136932 Free Article

19. Using induced pluripotent stem cells as a tool for modelling carcinogenesis. Curry EL, Moad M, Robson CN, Heer R. World J Stem Cells. 2015 Mar 26;7(2):461-9. doi: 10.4252/wjsc.v7.i2.461. Review. PMID: 25815129 Free PMC Article

20. Understanding the roadmaps to induced pluripotency. Liu K, Song Y, Yu H, Zhao T. Cell Death Dis. 2014 May 15;5:e1232. doi: 10.1038/cddis.2014.205. Review. PMID: 24832604 Free PMC Article

21. Human induced pluripotent stem cells--from mechanisms to clinical applications. Drews K, Jozefczuk J, Prigione A, Adjaye J. J Mol Med (Berl). 2012 Jul;90(7):735-45. doi: 10.1007/s00109-012-0913-0. Epub 2012 May 30. Review. PMID: 22643868

22. Stem cell marker OCT3/4 in tumor biology and germ cell tumor diagnostics: history and future. de Jong J, Looijenga LH. Crit Rev Oncog. 2006 Dec;12(3-4):171-203. Review. PMID: 17425502

23. Octamer-binding transcription factors: genomics and functions. Zhao FQ. Front Biosci (Landmark Ed). 2013 Jun 1;18:1051-71. Review. PMID: 23747866 Free PMC Article

24. Do all roads lead to Oct4? the emerging concepts of induced pluripotency. Radzisheuskaya A, Silva JC. Trends Cell Biol. 2014 May;24(5):275-84. doi: 10.1016/j.tcb.2013.11.010. Epub 2013 Dec 23. Review. PMID: 24370212 Free PMC Article

25. OCT4: dynamic DNA binding pioneers stem cell pluripotency. Jerabek S, Merino F, Schöler HR, Cojocaru V. Biochim Biophys Acta. 2014 Mar;1839(3):138-54. doi: 10.1016/j.bbagrm.2013.10.001. Epub 2013 Oct 18. Review. PMID: 24145198

26. Characterization of a novel cell penetrating peptide derived from human Oct4.

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27. KLF4, p21 and context-dependent opposing forces in cancer. Rowland BD, Peeper DS. Nat Rev Cancer. 2006 Jan;6(1):11-23. Review. PMID: 16372018

28. The diverse functions of Krüppel-like factors 4 and 5 in epithelial biology and pathobiology. McConnell BB, Ghaleb AM, Nandan MO, Yang VW. Bioessays. 2007 Jun;29(6):549-57. Review. Erratum in: Bioessays. 2007 Sep;29(9):946. PMID: 17508399 Free PMC Article

29. Role of Krüppel-like factor 4 and its binding proteins in vascular disease. Yoshida T, Hayashi M. J Atheroscler Thromb. 2014;21(5):402-13. Epub 2014 Mar 26. Review. PMID: 24573018 Free Article

30. Role of SOX family of transcription factors in central nervous system tumors. de la Rocha AM, Sampron N, Alonso MM, Matheu A. Am J Cancer Res. 2014 Jul 16;4(4):312-24. eCollection 2014. Review. PMID: 25057435 Free PMC Article

31. Sox2 transcription network acts as a molecular switch to regulate properties of neural stem cells. Shimozaki K. World J Stem Cells. 2014 Sep 26;6(4):485-90. doi: 10.4252/wjsc.v6.i4.485. Review. PMID: 25258670 Free PMC Article

32. Sox2, a key factor in the regulation of pluripotency and neural differentiation. Zhang S, Cui W. World J Stem Cells. 2014 Jul 26;6(3):305-11. doi: 10.4252/wjsc.v6.i3.305. Review. PMID: 25126380 Free PMC Article

33. Cellular reprogramming employing recombinant sox2 protein. Thier M, Münst B, Mielke S, Edenhofer F. Stem Cells Int. 2012;2012:549846. doi: 10.1155/2012/549846. Epub 2012 May 29. PMID: 22693519 Free PMC Article

34. MYC cofactors: molecular switches controlling diverse biological outcomes. Hann SR. Cold Spring Harb Perspect Med. 2014 Jun 17;4(9):a014399. doi: 10.1101/cshperspect.a014399. Review. PMID: 24939054

35. MYC and the control of apoptosis. McMahon SB. Cold Spring Harb Perspect Med. 2014 Jul 1;4(7):a014407. doi: 10.1101/cshperspect.a014407. Review. PMID: 24985130

36. Roles for MYC in the establishment and maintenance of pluripotency. Chappell J, Dalton S. Cold Spring Harb Perspect Med. 2013 Dec 1;3(12):a014381. doi: 10.1101/cshperspect.a014381. Review. PMID: 24296349