User:Mhirabay/sandbox

MyoD is a protein with a key role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins known as myogenic regulatory factors (MRFs). These bHLH (basic helix loop helix) transcription factors act sequentially in myogenic differentiation. MRF family members include MyoD, Myf5, myogenin, and MRF4 (Myf6).

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 activated expression of MyoD in response to exercise or muscle tissue damage. The effect of MyoD on satellite cells though is dose-dependent though because high MyoD expression represses cell renewal and induces apoptosis. Although MyoD marks myoblast commitment, muscle development is not dramatically ablated in mouse mutants lacking the MyoD gene. This is likely to be due to functional redundancy from Myf5. Nevertheless, the combination of MyoD and Myf5 is vital to the success of myogenesis. MyoD is also an important effector for the fast-twitch muscle fiber (type IIa and IIx) phenotype.

History

MyoD was first described as a nuclear phosphoprotein in 1988 by Tapscott, Davis, Thayer, Cheng, Weintraub, and Lassar in a Science article on October 21st. The researchers expressed the complementary DNA (cDNA) of the mouse MyoD protein in a different cell lines (fibroblast and adipoblast) and found MyoD converted them to myogenic cell. 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. 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 play a role in regulating 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 myoblasts) by enhancing the transcription of p21. 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.

Mechanisms

MyoD is known to have binding interactions with hundreds of muscular gene promoters and drive myoblast proliferation. While not completely understood, it is now thought that MyoD fuctions as the ultimate myogenesis controller in an on/off switch association mediated by KAP1 (KRAB [Krüppel-like associated box]-associated protein 1) phosphorylation. 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 whoce include G9a and the Histone deacetylase HDAC1. The resulting consequence of the 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.

Once the "master controller" MyoD has become active, it is apparant the SETDB1 is required for maintained 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. In Setdb1 depleted myoblasts that are treated with exogenous MyoD, myoblastic differentiation is succesfully restored. In one model of Setdb1 action on MyoD, Setdb1 represses an inhibitor of MyoD. This unidentified inhibitor likely acts competetively 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.

Evidence suggests that Stdb1 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 proto-oncogene, Retinoblastoma protein (pRb) to cause cell cycle arrest in the terminally differentiated myoblasts. 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 supresses the enhancer, therefore suppressing cyclin D1 and ultimately resulting in cell cycle arrest for terminally differentiated myoblasts.

Role in the wnt signalling pathway

The Wnt signalling pathway family refers to a group of secreted paracrine signaling proteins. There have been 19 glycoproteins identified to comprise this family. Wnts bind to the plasma membrane receptor Frizzled on the target cells. There are several different intracellular pathways of signalling that the Wnts may activate upon interacting with the Frizzled receptor. ONe of the most common is of which is inhibition of glycogen synthase kinase 3β (GSK3β) which functions to destroy Beta-catenin. This inhibition allows β-catenin to accumulate in the cell cytoplasm and eventual importation into the nucleus. In the canonical Wnt pathway (which is the most completely understood), nuclear β-catenin forms a dimer with T-cell factor (TCF) and lympoid enhaner factor (LEF) on the gene promoter that is targeted. This initiates transcription and mediates the physiological response to the initial Wnt signal. Wnt-Frizzled pathways also are known to activate c-Jun N-terminal kinases (JNKs) in the cytoplasm. Wnts also drive the translocation of T-cells (NFATs) in the nucleus to also initiate the transcription of the targeted genes.

Proteins involved in the Wnt signalling pathway induce cells in somites and competent tissues that receive these wnt signals to actively express Pax3 and Pax7 in addition to myogenic regulatory factors, including Myf5 and MyoD. Specifically, Wnt3a is responsible for direct induction of MyoD expression via cis-elements interactions with a distal enhancer and Wnt response element.

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. It is clear then that Wnt places a crucial role in satellite cell regulation and skeletal muscle aging and also regeneration. Wnta are known to active the expression of Myf5 and MyoD by Wnt1 and Wnt7a respectively. 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. It has been not fully understood though if MyoD is activated by Wnt via cis-regulation direct targeting or through indirect physiological pathways.

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.

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 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. Due to NFATc1 physically disrupting the interaction with p300, this establishes the molecular mechanism by witch fiber types are transition in vivo through exercise by opposite roles of NFATc1 and MyoD and the way NFATc1 controls this balance by physical inhibition of MyoD in slow-twitch muscle fiber types.

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 an 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. 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 activatiom of muscle gene that is condition-specific and established by MyoD recuitment. 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 factors- enhancer complex to assume a transcriptionally active state.

Interactions

MyoD has been shown to interact with:

• C-jun,
• CREBBP,
• CSRP3,
• CDK4,
• CDKN1C,
• EP300,
• HDAC1,
• ID1,
• ID2,
• MDFI,
• MOS,
• NR2B1
• RB1,
• STAT3, and
• TCF3.

Further reading

• Weintraub H, Davis R, Tapscott S, Thayer M, Krause M, Benezra R, Blackwell TK, Turner D, Rupp R, Hollenberg S (1991). "The myoD gene family: nodal point during specification of the muscle cell lineage". Science. 251 (4995): 761–6. doi:10.1126/science.1846704. PMID 1846704.
• Tapscott SJ, Weintraub H (1991). "MyoD and the regulation of myogenesis by helix-loop-helix proteins". J. Clin. Invest. 87 (4): 1133–8. doi:10.1172/JCI115109. PMC 295115. PMID 1849142.
• Olson EN (1990). "MyoD family: a paradigm for development?". Genes Dev. 4 (9): 1454–61. doi:10.1101/gad.4.9.1454. PMID 2253873.
• Goldman PS, Tran VK, Goodman RH (1997). "The multifunctional role of the co-activator CBP in transcriptional regulation". Recent Prog. Horm. Res. 52: 103–19, discussion 119-20. PMID 9238849.
• Puri PL, Sartorelli V (2000). "Regulation of muscle regulatory factors by DNA-binding, interacting proteins, and post-transcriptional modifications". J. Cell. Physiol. 185 (2): 155–73. doi:10.1002/1097-4652(200011)185:2<155::AID-JCP1>3.0.CO;2-Z. PMID 11025438.
• McKinsey TA, Zhang CL, Olson EN (2001). "Control of muscle development by dueling HATs and HDACs". Curr. Opin. Genet. Dev. 11 (5): 497–504. doi:10.1016/S0959-437X(00)00224-0. PMID 11532390.
• Berkes CA, Tapscott SJ (2006). "MyoD and the transcriptional control of myogenesis". Semin. Cell Dev. Biol. 16 (4–5): 585–95. doi:10.1016/j.semcdb.2005.07.006. PMID 16099183.
• Bengal E, Ransone L, Scharfmann R, Dwarki VJ, Tapscott SJ, Weintraub H, Verma IM (1992). "Functional antagonism between c-Jun and MyoD proteins: a direct physical association". Cell. 68 (3): 507–19. doi:10.1016/0092-8674(92)90187-H. PMID 1310896. S2CID 44966899.
• Walsh K, Gualberto A (1992). "MyoD binds to the guanine tetrad nucleic acid structure". J. Biol. Chem. 267 (19): 13714–8. doi:10.1016/S0021-9258(18)42272-7. PMID 1320026.
• Li L, Zhou J, James G, Heller-Harrison R, Czech MP, Olson EN (1992). "FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains". Cell. 71 (7): 1181–94. doi:10.1016/S0092-8674(05)80066-2. PMID 1335366. S2CID 32701560.
• Shaknovich R, Shue G, Kohtz DS (1992). "Conformational activation of a basic helix-loop-helix protein (MyoD1) by the C-terminal region of murine HSP90 (HSP84)". Mol. Cell. Biol. 12 (11): 5059–68. doi:10.1128/mcb.12.11.5059. PMC 360439. PMID 1406681.
• Lassar AB, Davis RL, Wright WE, Kadesch T, Murre C, Voronova A, Baltimore D, Weintraub H (1991). "Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12/E47-like proteins in vivo". Cell. 66 (2): 305–15. doi:10.1016/0092-8674(91)90620-E. PMID 1649701. S2CID 25957022.
• Pearson-White SH (1991). "Human MyoD: cDNA and deduced amino acid sequence". Nucleic Acids Res. 19 (5): 1148. doi:10.1093/nar/19.5.1148. PMC 333794. PMID 1850513.
• Gessler M, Hameister H, Henry I, Junien C, Braun T, Arnold HH (1990). "The human MyoD1 (MYF3) gene maps on the short arm of chromosome 11 but is not associated with the WAGR locus or the region for the Beckwith-Wiedemann syndrome". Hum. Genet. 86 (2): 135–8. doi:10.1007/bf00197694. PMID 2176177. S2CID 2051733.
• Scrable HJ, Johnson DK, Rinchik EM, Cavenee WK (1990). "Rhabdomyosarcoma-associated locus and MYOD1 are syntenic but separate loci on the short arm of human chromosome 11". Proc. Natl. Acad. Sci. U.S.A. 87 (6): 2182–6. doi:10.1073/pnas.87.6.2182. PMC 53650. PMID 2315312.
• Lassar AB, Buskin JN, Lockshon D, Davis RL, Apone S, Hauschka SD, Weintraub H (1989). "MyoD is a sequence-specific DNA binding protein requiring a region of myc homology to bind to the muscle creatine kinase enhancer". Cell. 58 (5): 823–31. doi:10.1016/0092-8674(89)90935-5. PMID 2550138. S2CID 27065049.
• Braun T, Bober E, Buschhausen-Denker G, Kohtz S, Grzeschik KH, Arnold HH, Kotz S (1989). "Differential expression of myogenic determination genes in muscle cells: possible autoactivation by the Myf gene products". EMBO J. 8 (12): 3617–25. doi:10.1002/j.1460-2075.1989.tb08535.x. PMC 402043. PMID 2583111.

External links

• MyoD+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

Category:Human genes Category:Transcription factors Category:Human proteins

Ideas and Articles

I was thinking of either expanding the article on MyoD (specific expansions discussed in the talk page) or EGR3

Here are the articles:

• This one is very new and discuses cell reprogramming with MyoD: Yang X, Malik V, Jauch R (Jan 2015). "Reprogramming cells with synthetic proteins". Asian Journal of Andrology. 17 (3): 394–402. doi:10.4103/1008-682X.145433. PMC 4430937. PMID 25652623.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• This one is neat because it talks about MyoD in connection with Wnt Signalling: Pan YC, Wang XW, Teng HF, Wu YJ, Chang HC, Chen SL (Feb 2015). "Wnt3a signal pathways activate MyoD expression by targeting cis-elements inside and outside its distal enhancer". Bioscience Reports. 35 (2). doi:10.1042/BSR20140177. PMC 4370097. PMID 25651906.
• These two articles discuss EGR3 in relation to cancers (Ras-Signaling)
  • Baron VT, Pio R, Jia Z, Mercola D (Feb 2015). "Early Growth Response 3 regulates genes of inflammation and directly activates IL6 and IL8 expression in prostate cancer". British Journal of Cancer. 112 (4): 755–764. doi:10.1038/bjc.2014.622. PMC 4333488. PMID 25633035.
  • Salotti J, Sakchaisri K, Tourtellotte WG, Johnson PF (Mar 2015). "An Arf-Egr-C/EBPβ Pathway Linked to Ras-Induced Senescence and Cancer". Molecular and Cellular Biology. 35 (5): 866–883. doi:10.1128/MCB.01489-14. PMC 4323493. PMID 25535333.