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AP-1 transcription factor
An instance of defined set in Homo sapiens with Reactome ID (R-HSA-6806560)

Activator protein 1 (AP-1) is a transcription factor that regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections. AP-1 controls a number of cellular processes including differentiation, proliferation, and apoptosis. The structure of AP-1 is a heterodimer composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families.

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History

AP-1 was first discovered as a TPA-activated transcription factor that bound to a cis-regulatory element of the human metallothionein IIa (hMTIIa) promoter and SV40.3 The AP-1 binding site was identified as the 12-O-Tetradecanoylphorbol-13-acetate (TPA) response element (TRE) with the consensus sequence 5’-TGA G/C TCA-3’.4 The AP-1 subunit Jun was identified as a novel oncoprotein of avian sarcoma virus, and Fos-associated p39 protein was identified as the transcript of the cellular Jun gene. Fos was first isolated as the cellular homologue of two viral v-fos oncogenes, both of which induce osteosarcoma in mice and rats.5 Since its discovery, AP-1 has been found to be associated with numerous regulatory and physiological processes, and new relationships are still being investigated.

Structure

AP-1 transcription factor is assembled through the dimerization of a characteristic bZIP domain (basic region leucine zipper) in the Fos and Jun subunits. A typical bZIP domain consists of a “leucine zipper” region, and a “basic region”. The leucine zipper is responsible for dimerization of the Jun and Fos protein subunits. This structural motif twists two alpha helical protein domains into a “coiled coil,” characterized by a periodicity of 3.5 residues per turn and repetitive leucines appearing at every seventh position of the polypeptide chain. Due to the amino acid sequence and the periodicity of the helices, the leucine side chains are arranged along one face of the α helix and form a hydrophobic surface that modulates dimerization.6 Hydrophobic residues additional to leucine also form the characteristic 3-4 repeat of α helices involved in “coiled-coil” interactions, and help contribute to the hydrophobic packing that drives dimerization. Together, this hydrophobic surface holds the two subunits together.78

The basic region of the bZIP domain is just upstream to the leucine zipper, and contains positively charged residues. This region interacts with DNA target sites.9 Apart from the “leucine zipper” and the “basic region” which are important for dimerization and DNA-binding, the c-jun protein contains three short regions, which consist of clusters of negatively charged amino acids in its N-terminal half that are important for transcriptional activation in vivo.10

Dimerization happens between the products of the c-jun and c-fos protooncogenes, and is required for DNA-binding. Jun proteins can form both homo and heterodimers and therefore are capable of binding to DNA by themselves. However, Fos proteins do not dimerize with each other and therefore can only bind to DNA when bound with Jun.1112 The Jun-Fos heterodimer is more stable and has higher DNA-binding activity than Jun homodimers.

Function

AP-1 transcription factor has been shown to have a hand in a wide range of cellular processes, including cell growth, differentiation, and apoptosis. AP-1 activity is often regulated via post-translational modifications, DNA binding dimer composition, and interaction with various binding partners. AP-1 transcription factors are also associated with numerous physiological functions especially in determination of organisms’ life span and tissue regeneration. Below are some of the other important functions and biological roles AP-1 transcription factors have been shown to be involved in.

Cell growth, proliferation and senescence

The AP-1 transcription factor has been shown to play numerous roles in cell growth and proliferation. In particular, c-Fos and c-Jun seem to be major players in these processes. C-jun has been shown to be essential for fibroblast proliferation,13 and levels of both AP-1 subunits have been shown to be expressed above basal levels during cell division.14 C-fos has also been shown to increase in expression in response to the introduction of growth factors in the cell, further supporting its suggested involvement in the cell cycle. The growth factors TGF alpha, TGF beta, and IL2 have all been shown to stimulate c-Fos, and thereby stimulate cellular proliferation via AP-1 activation.15

Cellular senescence has been identified as "a dynamic and reversible process regulated by (in)activation of a predetermined enhancer landscape controlled by the pioneer transcription factor AP-1", which "defines the organizational principles of the transcription factor network that drives the transcriptional programme of senescent cells".1617

Cellular differentiation

AP-1 transcription is deeply involved in the modulation of gene expression. Changes in cellular gene expression in the initiation of DNA synthesis and the formation of differentiated derivatives can lead to cellular differentiation.18 AP-1 has been shown to be involved in cell differentiation in several systems. For example, by forming stable heterodimers with c-Jun, the bZIP region of c-Fos increases the binding of c-Jun to target genes whose activation is involved in the differentiation of chicken embryo fibroblasts (CEF).19 It has also been shown to participate in endoderm specification.20

Apoptosis

AP-1 transcription factor is associated with a broad range of apoptosis related interactions. AP-1 activity is induced by numerous extracellular matrix and genotoxic agents, suggesting involvement in programmed cell death.21 Many of these stimuli activate the c-Jun N-terminal kinases (JNKs) leading to the phosphorylation of Jun proteins and enhanced transcriptional activity of AP-1 dependent genes.22 Increases in the levels of Jun and Fos proteins and JNK activity have been reported in scenarios in which cells undergo apoptosis. For example, inactivated c-Jun-ER cells show a normal morphology, while c-Jun-ER activated cells have been shown to be apoptotic.23

tissue specific regulation

It has been shown that AP-1 motif regulates tissue-specific genes through enhancer selection mechanism in fibroblasts. 24 It has been shown that AP-1 motif is related to epigenetic regulation in kidney function 25 and now there is suspect that AP-1 motif is regulated in developing RPE, specifically through OTX2.

Regulation of AP-1

Increased AP-1 levels lead to increased transactivation of target gene expression. Regulation of AP-1 activity is therefore critical for cell function and occurs through specific interactions controlled by dimer-composition, transcriptional and post-translational events, and interaction with accessory proteins.26

AP-1 functions are heavily dependent on the specific Fos and Jun subunits contributing to AP-1 dimers.27 The outcome of AP-1 activation is dependent on the complex combinatorial patterns of AP-1 component dimers.28 The AP-1 complex binds to a palindromic DNA motif (5’-TGA G/C TCA-3’) to regulate gene expression, but specificity is dependent on the dimer composition of the bZIP subunit.29

Physiological relevance

AP-1 transcription factor has been shown to be involved in skin physiology, specifically in tissue regeneration. The process of skin metabolism is initiated by signals that trigger undifferentiated proliferative cells to undergo cell differentiation. Therefore, activity of AP-1 subunits in response to extracellular signals may be modified under conditions where the balance of keratinocyte proliferation and differentiation has to be rapidly and temporally altered.30 The AP-1 transcription factor also has been shown to be involved in breast cancer cell growth through multiple mechanisms, including regulation of cyclin D1, E2F factors and their target genes. c-Jun, which is one of the AP-1 subunits, regulates the growth of breast cancer cells. Activated c-Jun is predominantly expressed at the invasive front in breast cancer and is associated with proliferation of breast cells.31 Due to the AP-1 regulatory functions in cancer cells, AP-1 modulation is studied as a potential strategy for cancer prevention and therapy.323334

Regulome

See also

References

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  2. Ameyar M, Wisniewska M, Weitzman JB (August 2003). "A role for AP-1 in apoptosis: the case for and against". Biochimie. 85 (8): 747–52. doi:10.1016/j.biochi.2003.09.006. PMID 14585541. /wiki/Doi_(identifier) ↩

  3. Lee W, Haslinger A, Karin M, Tjian R (January 1987). "Activation of transcription by two factors that bind promoter and enhancer sequences of the human metallothionein gene and SV40". Nature. 325 (6102): 368–72. Bibcode:1987Natur.325..368L. doi:10.1038/325368a0. PMID 3027570. S2CID 4314423. /wiki/Bibcode_(identifier) ↩

  4. Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrlich P, Karin M (June 1987). "Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor". Cell. 49 (6): 729–39. doi:10.1016/0092-8674(87)90611-8. PMID 3034432. S2CID 23154076. /wiki/Doi_(identifier) ↩

  5. Wagner EF (April 2001). "AP-1--Introductory remarks". Oncogene. 20 (19): 2334–5. doi:10.1038/sj.onc.1204416. PMID 11402330. https://doi.org/10.1038%2Fsj.onc.1204416 ↩

  6. Landschulz WH, Johnson PF, McKnight SL (June 1988). "The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins". Science. 240 (4860): 1759–64. Bibcode:1988Sci...240.1759L. doi:10.1126/science.3289117. PMID 3289117. /wiki/Bibcode_(identifier) ↩

  7. O'Shea EK, Rutkowski R, Kim PS (January 1989). "Evidence that the leucine zipper is a coiled coil". Science. 243 (4890): 538–42. Bibcode:1989Sci...243..538O. doi:10.1126/science.2911757. PMID 2911757. /wiki/Bibcode_(identifier) ↩

  8. O'Shea EK, Rutkowski R, Stafford WF, Kim PS (August 1989). "Preferential heterodimer formation by isolated leucine zippers from fos and jun". Science. 245 (4918): 646–8. Bibcode:1989Sci...245..646O. doi:10.1126/science.2503872. PMID 2503872. /wiki/Bibcode_(identifier) ↩

  9. Vogt PK, Bos TJ (1990). "jun: oncogene and transcription factor". Advances in Cancer Research. 55: 1–35. doi:10.1016/s0065-230x(08)60466-2. ISBN 9780120066551. PMID 2166997. 9780120066551 ↩

  10. Angel P, Karin M (December 1991). "The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1072 (2–3): 129–57. doi:10.1016/0304-419X(91)90011-9. PMID 1751545. /wiki/Doi_(identifier) ↩

  11. Kouzarides T, Ziff E (December 1988). "The role of the leucine zipper in the fos-jun interaction". Nature. 336 (6200): 646–51. Bibcode:1988Natur.336..646K. doi:10.1038/336646a0. PMID 2974122. S2CID 4355663. /wiki/Bibcode_(identifier) ↩

  12. Nakabeppu Y, Ryder K, Nathans D (December 1988). "DNA binding activities of three murine Jun proteins: stimulation by Fos". Cell. 55 (5): 907–15. doi:10.1016/0092-8674(88)90146-8. PMID 3142691. S2CID 11057487. /wiki/Doi_(identifier) ↩

  13. Karin M, Liu Z, Zandi E (April 1997). "AP-1 function and regulation". Current Opinion in Cell Biology. 9 (2): 240–6. doi:10.1016/S0955-0674(97)80068-3. PMID 9069263. /wiki/Doi_(identifier) ↩

  14. Yamashita J, McCauley LK (2006). "The Activating Protein-1 Transcriptional Complex: Essential and Multifaceted Roles in Bone". Clinical Reviews in Bone and Mineral Metabolism. 4 (2): 107–122. doi:10.1385/BMM:4:2:107. S2CID 90318354. /wiki/Doi_(identifier) ↩

  15. Angel P, Karin M (December 1991). "The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1072 (2–3): 129–57. doi:10.1016/0304-419X(91)90011-9. PMID 1751545. /wiki/Doi_(identifier) ↩

  16. Zumerle S, Alimonti A (2020). "In and out from senescence". Nat Cell Biol. 22 (7): 753–754. doi:10.1038/s41556-020-0540-x. PMID 32591745. S2CID 220071911. https://doi.org/10.1038%2Fs41556-020-0540-x ↩

  17. Martínez-Zamudio R, Roux P, de Freitas J, et al. (2020). "AP-1 imprints a reversible transcriptional programme of senescent cells". Nat Cell Biol. 22 (7): 842–855. doi:10.1038/s41556-020-0529-5. PMC 7899185. PMID 32514071. S2CID 219543898. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899185 ↩

  18. Angel P, Karin M (December 1991). "The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1072 (2–3): 129–57. doi:10.1016/0304-419X(91)90011-9. PMID 1751545. /wiki/Doi_(identifier) ↩

  19. Shaulian E, Karin M (May 2002). "AP-1 as a regulator of cell life and death". Nature Cell Biology. 4 (5): E131–6. doi:10.1038/ncb0502-e131. PMID 11988758. S2CID 34337538. /wiki/Doi_(identifier) ↩

  20. Madrigal P, Deng S, Feng Y, Militi S, Goh KJ, Nibhani R, Grandy R, Osnato A, Ortmann D, Brown S, Pauklin S (January 25, 2023). "Epigenetic and transcriptional regulations prime cell fate before division during human pluripotent stem cell differentiation" (PDF). Nature Communications. 14 (405): 405. Bibcode:2023NatCo..14..405M. doi:10.1038/s41467-023-36116-9. PMC 9876972. PMID 36697417. https://www.nature.com/articles/s41467-023-36116-9.pdf ↩

  21. Ameyar M, Wisniewska M, Weitzman JB (August 2003). "A role for AP-1 in apoptosis: the case for and against". Biochimie. 85 (8): 747–52. doi:10.1016/j.biochi.2003.09.006. PMID 14585541. /wiki/Doi_(identifier) ↩

  22. Ameyar M, Wisniewska M, Weitzman JB (August 2003). "A role for AP-1 in apoptosis: the case for and against". Biochimie. 85 (8): 747–52. doi:10.1016/j.biochi.2003.09.006. PMID 14585541. /wiki/Doi_(identifier) ↩

  23. Bossy-Wetzel E, Bakiri L, Yaniv M (April 1997). "Induction of apoptosis by the transcription factor c-Jun". The EMBO Journal. 16 (7): 1695–709. doi:10.1093/emboj/16.7.1695. PMC 1169773. PMID 9130714. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1169773 ↩

  24. Vierbuchen T, Ling E, Cowley CJ, Couch CH, Wang X, Harmin DA, Roberts CW, Greenberg ME (December 2017). "AP-1 Transcription Factors and the BAF Complex Mediate Signal-Dependent Enhancer Selection". Mol Cell. 68 (6): 1067–1082.e12. doi:10.1016/j.molcel.2017.11.026. PMC 5744881. PMID 29272704. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744881 ↩

  25. Sagy N, Meyrom N, Beckerman P, Pleniceanu O, Bar DZ (February 2024). "Kidney-specific methylation patterns correlate with kidney function and are lost upon kidney disease progression". Clin Epigenetics. 16 (1): 27. doi:10.1186/s13148-024-01642-w. PMC 10863297. PMID 38347603. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10863297 ↩

  26. Vesely PW, Staber PB, Hoefler G, Kenner L (July 2009). "Translational regulation mechanisms of AP-1 proteins". Mutation Research. 682 (1): 7–12. Bibcode:2009MRRMR.682....7V. doi:10.1016/j.mrrev.2009.01.001. PMID 19167516. /wiki/Bibcode_(identifier) ↩

  27. Angel P, Karin M (December 1991). "The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1072 (2–3): 129–57. doi:10.1016/0304-419X(91)90011-9. PMID 1751545. /wiki/Doi_(identifier) ↩

  28. Ameyar M, Wisniewska M, Weitzman JB (August 2003). "A role for AP-1 in apoptosis: the case for and against". Biochimie. 85 (8): 747–52. doi:10.1016/j.biochi.2003.09.006. PMID 14585541. /wiki/Doi_(identifier) ↩

  29. Ameyar M, Wisniewska M, Weitzman JB (August 2003). "A role for AP-1 in apoptosis: the case for and against". Biochimie. 85 (8): 747–52. doi:10.1016/j.biochi.2003.09.006. PMID 14585541. /wiki/Doi_(identifier) ↩

  30. Angel P, Szabowski A, Schorpp-Kistner M (April 2001). "Function and regulation of AP-1 subunits in skin physiology and pathology". Oncogene. 20 (19): 2413–23. doi:10.1038/sj.onc.1204380. PMID 11402337. https://doi.org/10.1038%2Fsj.onc.1204380 ↩

  31. Shen Q, Uray IP, Li Y, Krisko TI, Strecker TE, Kim HT, Brown PH (January 2008). "The AP-1 transcription factor regulates breast cancer cell growth via cyclins and E2F factors". Oncogene. 27 (3): 366–77. doi:10.1038/sj.onc.1210643. PMID 17637753. https://doi.org/10.1038%2Fsj.onc.1210643 ↩

  32. Eferl R, Wagner EF (November 2003). "AP-1: a double-edged sword in tumorigenesis". Nature Reviews. Cancer. 3 (11): 859–68. doi:10.1038/nrc1209. PMID 14668816. S2CID 35328722. /wiki/Doi_(identifier) ↩

  33. Tewari D, Nabavi SF, Nabavi SM, Sureda A, Farooqi AA, Atanasov AG, Vacca RA, Sethi G, Bishayee A (February 2018). "Targeting activator protein 1 signaling pathway by bioactive natural agents: Possible therapeutic strategy for cancer prevention and intervention". Pharmacological Research. 128: 366–375. doi:10.1016/j.phrs.2017.09.014. PMID 28951297. S2CID 20160666. /wiki/Doi_(identifier) ↩

  34. Kamide D, Yamashita T, Araki K, Tomifuji M, Tanaka Y, Tanaka S, Shiozawa S, Shiotani A (May 2016). "Selective activator protein-1 inhibitor T-5224 prevents lymph node metastasis in an oral cancer model". Cancer Science. 107 (5): 666–73. doi:10.1111/cas.12914. PMC 4970834. PMID 26918517. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970834 ↩

  35. Bahrami S, Drabløs F (2016). "Gene regulation in the immediate-early response process". Advances in Biological Regulation. 62: 37–49. doi:10.1016/j.jbior.2016.05.001. PMID 27220739. https://doi.org/10.1016%2Fj.jbior.2016.05.001 ↩