Biology:MyoD

From HandWiki
Revision as of 08:28, 9 May 2023 by WikiG (talk | contribs) (over-write)
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

MyoD, also known as myoblast determination protein 1,[1] is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub,[2] belongs to a family of proteins known as myogenic regulatory factors (MRFs).[3] These bHLH (basic helix loop helix) transcription factors act sequentially in myogenic differentiation. Vertebrate MRF family members include MyoD1, Myf5, myogenin, and MRF4 (Myf6). In non-vertebrate animals, a single MyoD protein is typically found.

MyoD is one of the earliest markers of myogenic commitment. MyoD is expressed at extremely low and essentially undetectable levels in quiescent satellite cells, but expression of MyoD is activated in response to exercise or muscle tissue damage. The effect of MyoD on satellite cells is dose-dependent; high MyoD expression represses cell renewal, promotes terminal differentiation and can induce apoptosis. Although MyoD marks myoblast commitment, muscle development is not dramatically ablated in mouse mutants lacking the MyoD gene. This is likely due to functional redundancy from Myf5 and/or Mrf4. Nevertheless, the combination of MyoD and Myf5 is vital to the success of myogenesis.[4][5]

History

MyoD was cloned by a functional assay for muscle formation reported in Cell in 1987 by Davis, Weintraub, and Lassar. It was first described as a nuclear phosphoprotein in 1988 by Tapscott, Davis, Thayer, Cheng, Weintraub, and Lassar in Science. The researchers expressed the complementary DNA (cDNA) of the murine MyoD protein in a different cell lines (fibroblast and adipoblast) and found MyoD converted them to myogenic cells.[2][6] The following year, the same research team performed several tests to determine both the structure and function of the protein, confirming their initial proposal that the active site of the protein consisted of the helix loop helix (now referred to as basic helix loop helix) for dimerization and a basic site upstream of this bHLH region facilitated DNA binding only once it became a protein dimer.[7] MyoD has since been an active area of research as still relatively little is known concerning many aspects of its function.

Function

The function of MyoD in development is to commit mesoderm cells to a skeletal myoblast lineage, and then to regulate that continued state. MyoD may also regulate muscle repair. MyoD mRNA levels are also reported to be elevated in aging skeletal muscle.

One of the main actions of MyoD is to remove cells from the cell cycle (halt proliferation for terminal cell cycle arrest in differentiated myocytes) by enhancing the transcription of p21 and myogenin. MyoD is inhibited by cyclin dependent kinases (CDKs). CDKs are in turn inhibited by p21. Thus MyoD enhances its own activity in the cell in a feedforward manner.

Sustained MyoD expression is necessary for retaining the expression of muscle-related genes.[8]

MyoD is also an important effector for the fast-twitch muscle fiber (types IIA, IIX, and IIB) phenotype.[9][10]

Mechanisms

MyoD is a transcription factor and can also direct chromatin remodelling through binding to a DNA motif known as the E-box. MyoD is known to have binding interactions with hundreds of muscular gene promoters and to permit myoblast proliferation. While not completely understood, MyoD is now thought to function as a major myogenesis controller in an on/off switch association mediated by KAP1 (KRAB [Krüppel-like associated box]-associated protein 1) phosphorylation.[11] KAP1 is localized at muscle-related genes in myoblasts along with both MyoD and Mef2 (a myocyte transcription enhancer factor). Here, it serves as a scaffold and recruits the coactivators p300 and LSD1, in addition to several corepressors which include G9a and the Histone deacetylase HDAC1. The consequence of this coactivator/corepressor recruitment is silenced promoting regions on muscle genes. When the kinase MSK1 phosphorylates KAP1, the corepressors previously bound to the scaffold are released allowing MyoD and Mef2 to activate transcription.[12]

Once the "master controller" MyoD has become active, SETDB1 is required to maintain MyoD expression within the cell. Setdb1 appears to be necessary to maintain both MyoD expression and also genes that are specific to muscle tissues because reduction of Setdb1 expression results in a severe delay of myoblast differentiation and determination.[13] In Setdb1 depleted myoblasts that are treated with exogenous MyoD, myoblastic differentiation is successfully restored. In one model of Setdb1 action on MyoD, Setdb1 represses an inhibitor of MyoD. This unidentified inhibitor likely acts competitively against MyoD during typical cellular proliferation. Evidence for this model is that reduction of Setdb1 results in direct inhibition of myoblast differentiation which may be caused by the release of the unknown MyoD inhibitor.

Stdb1/MyoD possible pathway.
Evidence suggests that Setdb1 inhibits a repressor of MyoD and this is the mechanism through which MyoD expression is retained in differentiated myoblasts.

MyoD has also been shown to function cooperatively with the tumor suppressor gene, Retinoblastoma (pRb) to cause cell cycle arrest in the terminally differentiated myoblasts.[14] This is done through regulation of the Cyclin, Cyclin D1. Cell cycle arrest (in which myoblasts would indicate the conclusion of myogenesis) is dependent on the continuous and stable repression of the D1 cyclin. Both MyoD and pRb are necessary for the repression of cyclin D1, but rather than acting directly on cyclin D1, they act on Fra-1 which is immediately early of cyclin D1. MyoD and pRb are both necessary for repressing Fra-1 (and thus cyclin D1) as either MyoD or pRb on its own is not sufficient alone to induce cyclin D1 repression and thus cell cycle arrest. In an intronic enhancer of Fra-1 there were two conserved MyoD binding sites discovered. There is cooperative action of MyoD and pRb at the Fra-1 intronic enhancer that suppresses the enhancer, therefore suppressing cyclin D1 and ultimately resulting in cell cycle arrest for terminally differentiated myoblasts.[15]

Wnt signalling can affect MyoD

Wnt signalling from adjacent tissues has been shown to induce cells in somites that receive these Wnt signals to express Pax3 and Pax7 in addition to myogenic regulatory factors, including Myf5 and MyoD. Specifically, Wnt3a can directly induce MyoD expression via cis-element interactions with a distal enhancer and Wnt response element.[16] Wnt1 from dorsal neural tube and Wnt6/Wnt7a from surface ectoderm have also been implicated in promoting myogenesis in the somite; the latter signals may act primarily through Myod.

In typical adult muscles in a resting condition (absence of physiological stress) the specific Wnt family proteins that are expressed are Wnt5a, Wnt5b, Wnt7a and Wnt4. When a muscle becomes injured (thus requiring regeneration) Wnt5a, Wnt5b, and Wnt7a are increased in expression. As the muscle completes repair Wnt7b and Wnt3a are increased as well. This patterning of Wnt signalling expression in muscle cell repair induces the differentiation of the progenitor cells, which reduces the number of available satellite cells. Wnt plays a crucial role in satellite cell regulation and skeletal muscle aging and also regeneration. Wnts are known to active the expression of Myf5 and MyoD by Wnt1 and Wnt7a. Wnt4, Wnt5, and Wnt6 function to increase the expression of both of the regulatory factors but at a more subtle level. Additionally, MyoD increases Wnt3a when myoblasts undergo differentiation. Whether MyoD is activated by Wnt via cis-regulation direct targeting or through indirect physiological pathways remains to be elucidated.[17]

Coactivators and repressors

IFRD1 is a positive cofactor of MyoD, as it cooperates with MyoD at inducing the transcriptional activity of MEF2C (by displacing HDAC4 from MEF2C); moreover IFRD1 also represses the transcriptional activity of NF-κB, which is known to inhibit MyoD mRNA accumulation.[18][19]

NFATc1 is a transcription factor that regulates composition of fiber type and the fast-to-slow twitch transition resulting from aerobic exercise requires the expression of NFATc1. MyoD expression is a key transcription factor in fast twitch fibers which is inhibited by NFATc1 in oxidative fiber types. NFATc1 works to inhibit MyoD via a physical interaction with the MyoD N-terminal activation domain resulting in inhibited recruitment of the necessary transcriptional coactivator p300. NFATc1 physically disrupts the interaction between MyoD and p300. This establishes the molecular mechanism by which fiber types transition in vivo through exercise with opposing roles for NFATc1 and MyoD. NFATc1 controls this balance by physical inhibition of MyoD in slow-twitch muscle fiber types.[20]

Recruitment of transcription factors by MyoD.
MyoD works with a transient placeholder protein that functions to prevent other transcription factors from binding to the DNA and also retains an inactive conformation for the DNA. Once the placeholder is removed (or possibly deactivated) the necessary transcription factors are free to bind and initiate recruitment of RNA Polymerase II and initiate active RNA transcription.

The histone deacetyltransferase p300 functions with MyoD in an interaction that is essential for the myotube generation from fibroblasts that is mediated by MyoD. Recruitment of p300 is the rate-limiting process in the conversion of fibroblasts to myotubes.[21] In addition to p300, MyoD is also known to recruit Set7, H3K4me1, H3K27ac, and RNAP II to the enhancer that is bound with and this allows for the activation of muscle gene that is condition-specific and established by MyoD recruitment. Endogenous p300 though, is necessary for MyoD functioning by acting as an essential coactivator. MyoD associatively binds to the enhancer region in conjunction with a placeholding "putative pioneer factor" which helps to establish and maintain a both of them in a specific and inactive conformation. Upon the removal or inactivation on the placeholder protein bound to the enhancer, the recruitment of the additional group of transcription factors that help to positively regulate enhancer activity is permitted and this results in the MyoD-transcription factor-enhancer complex to assume a transcriptionally active state.

Interactions

MyoD has been shown to interact with:


References

  1. ↑ "P15172 (MYOD1_HUMAN)". https://www.uniprot.org/uniprot/P15172. 
  2. ↑ 2.0 2.1 "Expression of a single transfected cDNA converts fibroblasts to myoblasts". Cell 51 (6): 987–1000. Dec 1987. doi:10.1016/0092-8674(87)90585-X. PMID 3690668. 
  3. ↑ "Entrez Gene: MYOD1 myogenic differentiation 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4654. 
  4. ↑ "MyoD or Myf-5 is required for the formation of skeletal muscle". Cell 75 (7): 1351–1359. Dec 1993. doi:10.1016/0092-8674(93)90621-V. PMID 8269513. 
  5. ↑ "Defective cranial skeletal development, larval lethality and haploinsufficiency in Myod mutant zebrafish". Dev. Biol. 358 (1): 102–112. Oct 2011. doi:10.1016/j.ydbio.2011.07.015. PMID 21798255. 
  6. ↑ "MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts". Science 242 (4877): 405–511. Oct 1988. doi:10.1126/science.3175662. PMID 3175662. Bibcode: 1988Sci...242..405T. 
  7. ↑ "MyoD and achaete-scute: 4-5 amino acids distinguishes myogenesis from neurogenesis". Princess Takamatsu Symposia 20: 267–278. 1989. PMID 2562185. 
  8. ↑ Fong, A; Tapscott, S (October 2014). "Skeletal muscle programming and re-programming". Current Opinion in Genetics & Development 23 (5): 568–573. doi:10.1016/j.gde.2013.05.002. PMID 23756045. 
  9. ↑ "MyoD protein is differentially accumulated in fast and slow skeletal muscle fibres and required for normal fibre type balance in rodents". Mech Dev 61 (1–2): 151–163. Jan 1997. doi:10.1016/S0925-4773(96)00631-4. PMID 9076685. 
  10. ↑ "NFATc1 controls skeletal muscle fiber type and is a negative regulator of MyoD activity". Cell Reports 8 (6): 1639–1648. Sep 2014. doi:10.1016/j.celrep.2014.08.035. PMID 25242327. 
  11. ↑ "A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation". Genes & Development 29 (5): 513–525. Mar 2015. doi:10.1101/gad.254532.114. PMID 25737281. 
  12. ↑ Buckingham, M; Rigby, P (February 2014). "Gene Regulatory Networks and Transcriptional Mechanisms that Control Myogenesis". Developmental Cell 28 (3): 225–238. doi:10.1016/j.devcel.2013.12.020. PMID 24525185. 
  13. ↑ "Setdb1 Is Required for Myogenic Differentiation of C2C12 Myoblast Cells via Maintenance of MyoD Expression". Molecules and Cells 38 (4): 362–372. Feb 2015. doi:10.14348/molcells.2015.2291. PMID 25715926. 
  14. ↑ "Retinoblastoma protein and MyoD function together to effect the repression of Fra-1 and in turn cyclin D1 during terminal cell cycle arrest associated with myogenesis". The Journal of Biological Chemistry 289 (34): 23417–23427. Aug 2014. doi:10.1074/jbc.M113.532572. PMID 25006242. 
  15. ↑ Milewska, M; Grabiec, K; Grzelkowska-Kowalczyk, K (May 2014). "[Interactions of proliferation and differentiation signaling pathways in myogenesis]". Postepy Hig Med Dosw 68: 516–526. doi:10.5604/17322693.1101617. PMID 24864103. 
  16. ↑ "Wnt3a signal pathways activate MyoD expression by targeting cis-elements inside and outside its distal enhancer". Bioscience Reports 35 (2): 1–12. Feb 2015. doi:10.1042/BSR20140177. PMID 25651906. 
  17. ↑ Motohashi, N.; Asakura, Atsushi (January 2014). "Muscle satellite cell heterogeneity and self-renewal". Frontiers in Cell and Developmental Biology 2 (1): 1. doi:10.3389/fcell.2014.00001. PMID 25364710. 
  18. ↑ "PC4 coactivates MyoD by relieving the histone deacetylase 4-mediated inhibition of myocyte enhancer factor 2C". Mol. Cell. Biol. 25 (6): 2242–59. March 2005. doi:10.1128/MCB.25.6.2242-2259.2005. PMID 15743821. 
  19. ↑ "PC4/Tis7/IFRD1 stimulates skeletal muscle regeneration and is involved in myoblast differentiation as a regulator of MyoD and NF-kappaB". J. Biol. Chem. 286 (7): 5691–707. February 2011. doi:10.1074/jbc.M110.162842. PMID 21127072. 
  20. ↑ "NFATc1 controls skeletal muscle fiber type and is a negative regulator of MyoD activity". Cell Reports 8 (6): 1639–1648. Sep 2014. doi:10.1016/j.celrep.2014.08.035. PMID 25242327. 
  21. ↑ Sartorelli, V; Huang, J; Hamamori, Y; Kedes, L (February 1997). "Molecular mechanisms of myogenic coactivation by p300: direct interaction with the activation domain of MyoD and with the MADS box of MEF2C". Molecular Cell Biology 17 (2): 1010–1026. doi:10.1128/mcb.17.2.1010. PMID 9001254. 
  22. ↑ "Functional antagonism between c-Jun and MyoD proteins: a direct physical association". Cell 68 (3): 507–19. February 1992. doi:10.1016/0092-8674(92)90187-h. PMID 1310896. 
  23. ↑ "Interaction between acetylated MyoD and the bromodomain of CBP and/or p300". Mol. Cell. Biol. 21 (16): 5312–20. August 2001. doi:10.1128/MCB.21.16.5312-5320.2001. PMID 11463815. 
  24. ↑ 24.0 24.1 "Molecular mechanisms of myogenic coactivation by p300: direct interaction with the activation domain of MyoD and with the MADS box of MEF2C". Mol. Cell. Biol. 17 (2): 1010–26. February 1997. doi:10.1128/mcb.17.2.1010. PMID 9001254. 
  25. ↑ "Muscle LIM protein promotes myogenesis by enhancing the activity of MyoD". Mol. Cell. Biol. 17 (8): 4750–60. August 1997. doi:10.1128/mcb.17.8.4750. PMID 9234731. 
  26. ↑ "Direct inhibition of G(1) cdk kinase activity by MyoD promotes myoblast cell cycle withdrawal and terminal differentiation". EMBO J. 18 (24): 6983–93. December 1999. doi:10.1093/emboj/18.24.6983. PMID 10601020. 
  27. ↑ "Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4". EMBO J. 18 (4): 926–33. February 1999. doi:10.1093/emboj/18.4.926. PMID 10022835. 
  28. ↑ "Stabilization of MyoD by direct binding to p57(Kip2)". J. Biol. Chem. 275 (25): 18767–76. June 2000. doi:10.1074/jbc.M907412199. PMID 10764802. 
  29. ↑ "Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: RORalpha1 directly interacts with p300 and myoD". Nucleic Acids Res. 27 (2): 411–20. January 1999. doi:10.1093/nar/27.2.411. PMID 9862959. 
  30. ↑ "Class I histone deacetylases sequentially interact with MyoD and pRb during skeletal myogenesis". Mol. Cell 8 (4): 885–97. October 2001. doi:10.1016/s1097-2765(01)00373-2. PMID 11684023. 
  31. ↑ 31.0 31.1 "A role for histone deacetylase HDAC1 in modulating the transcriptional activity of MyoD: inhibition of the myogenic program". EMBO J. 20 (7): 1739–53. April 2001. doi:10.1093/emboj/20.7.1739. PMID 11285237. 
  32. ↑ "The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis". Nature 428 (6980): 328–32. March 2004. doi:10.1038/nature02329. PMID 15029197. Bibcode: 2004Natur.428..328G. 
  33. ↑ 33.0 33.1 33.2 "Differential interactions of Id proteins with basic-helix-loop-helix transcription factors". J. Biol. Chem. 272 (32): 19785–93. August 1997. doi:10.1074/jbc.272.32.19785. PMID 9242638. 
  34. ↑ "Detection and modulation in vivo of helix-loop-helix protein-protein interactions". J. Biol. Chem. 268 (1): 5–8. January 1993. doi:10.1016/S0021-9258(18)54105-3. PMID 8380166. 
  35. ↑ "Mmip1: a novel leucine zipper protein that reverses the suppressive effects of Mad family members on c-myc". Oncogene 16 (9): 1149–59. March 1998. doi:10.1038/sj.onc.1201634. PMID 9528857. 
  36. ↑ "The LIM-only protein DRAL/FHL2 interacts with and is a corepressor for the promyelocytic leukemia zinc finger protein". J. Biol. Chem. 277 (40): 37045–53. October 2002. doi:10.1074/jbc.M203336200. PMID 12145280. 
  37. ↑ "Id-1 induces proteasome-dependent degradation of the HBX protein". J. Mol. Biol. 382 (1): 34–43. September 2008. doi:10.1016/j.jmb.2007.06.020. PMID 18674781. 
  38. ↑ "I-mf, a novel myogenic repressor, interacts with members of the MyoD family". Cell 86 (5): 731–41. September 1996. doi:10.1016/s0092-8674(00)80148-8. PMID 8797820. 
  39. ↑ "Mos activates myogenic differentiation by promoting heterodimerization of MyoD and E12 proteins". Mol. Cell. Biol. 17 (2): 584–93. February 1997. doi:10.1128/mcb.17.2.584. PMID 9001211. 
  40. ↑ "Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation". Cell 72 (3): 309–24. February 1993. doi:10.1016/0092-8674(93)90110-c. PMID 8381715. 
  41. ↑ "Retinoic acid receptors and muscle b-HLH proteins: partners in retinoid-induced myogenesis". Oncogene 16 (26): 3369–78. July 1998. doi:10.1038/sj.onc.1201894. PMID 9692544. 
  42. ↑ "Reciprocal inhibition between MyoD and STAT3 in the regulation of growth and differentiation of myoblasts". J. Biol. Chem. 278 (45): 44178–87. November 2003. doi:10.1074/jbc.M304884200. PMID 12947115. 
  43. ↑ "MyoD-E12 heterodimers and MyoD-MyoD homodimers are equally stable". Biochemistry 36 (22): 6762–7. June 1997. doi:10.1021/bi970262m. PMID 9184158. 

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:MyoD&oldid=2872061"