91783PathwayHop Pathway in Cardiac DevelopmentThe transcription of DNA is aided in large part by something called "homeodomain transcription factors". They are a diverse group of DNA binding factors. In fact, genes which are created with the aid of homeodomain factors tend to conglomerate and are responsible for anterior-posterior patterning. There is much to be said as well regarding the development and growth of cardiac myocytes and homedomain transcription factors. Indeed, at the early stages of the cell differentiation of cardiac myoctes a delicate balance of joint expression of several factors is needed for correct development (namely: serum response factor (SRF), and GATA4) and a homeodomain factor known as Nkx2-5! The joint expression of the aforementioned factors is the critical in the development of myocytes as well as gene expression in the cardiac region. To underline the importance of the homeodomain transcription factors, note that an error in the Nkx2-5 gene has severe consequences, which include, though are not necessarily limited to, embryonic lethality, as well as severe problems in general heart development. To put all this in context of the pathway in question, Hop actually stands for (Homeodomain Only Protein). The Hop gene plays an important role in the cardiac development we have been describing, as it too encodes a homedomain factor which plays an important role at the onset stages of cardiac development. The Hop gene is downstream of the Mkx2-5 factor we discussed earlier, and similar to it, improper activation of Hop can lead to severe cardiac development issues. In mice for example, not have the Hop gene results in alterations to the cell cycle. In particular, cardiac cells are unable to exit the cycle at the correct stage and continue grow after normal developmental stage has finished.
There exists an interesting symbiosis between Hop and SRF. First, Hop regulates gene expression by either binding to SRF or by preventing SRF binding to DNA. This occurs because Hop does not have anything to bind to DNA with, and as such must have different methods to regulate gene expression. Second, when Hop blocks normal SRF binding, the results is that the activation of genes in the heart is affected and normal development does not occur. In a nutshell, what can be said about this tango action of SRF and Hop is this: during the first stages of development, what is observed is that the Hop interaction is one which results in a cessation of the differentiation processes which are induced by SRF. In the later stages, it appears that Hop reduces cell proliferation which is normally caused by SRF.PhysiologicalPW091899CenterPathwayVisualizationContext9217511001970#000099PathwayVisualization9165591783Hop Pathway in Cardiac DevelopmentThe transcription of DNA is aided in large part by something called "homeodomain transcription factors". They are a diverse group of DNA binding factors. In fact, genes which are created with the aid of homeodomain factors tend to conglomerate and are responsible for anterior-posterior patterning. There is much to be said as well regarding the development and growth of cardiac myocytes and homedomain transcription factors. Indeed, at the early stages of the cell differentiation of cardiac myoctes a delicate balance of joint expression of several factors is needed for correct development (namely: serum response factor (SRF), and GATA4) and a homeodomain factor known as Nkx2-5! The joint expression of the aforementioned factors is the critical in the development of myocytes as well as gene expression in the cardiac region. To underline the importance of the homeodomain transcription factors, note that an error in the Nkx2-5 gene has severe consequences, which include, though are not necessarily limited to, embryonic lethality, as well as severe problems in general heart development. To put all this in context of the pathway in question, Hop actually stands for (Homeodomain Only Protein). The Hop gene plays an important role in the cardiac development we have been describing, as it too encodes a homedomain factor which plays an important role at the onset stages of cardiac development. The Hop gene is downstream of the Mkx2-5 factor we discussed earlier, and similar to it, improper activation of Hop can lead to severe cardiac development issues. In mice for example, not have the Hop gene results in alterations to the cell cycle. In particular, cardiac cells are unable to exit the cycle at the correct stage and continue grow after normal developmental stage has finished.
There exists an interesting symbiosis between Hop and SRF. First, Hop regulates gene expression by either binding to SRF or by preventing SRF binding to DNA. This occurs because Hop does not have anything to bind to DNA with, and as such must have different methods to regulate gene expression. Second, when Hop blocks normal SRF binding, the results is that the activation of genes in the heart is affected and normal development does not occur. In a nutshell, what can be said about this tango action of SRF and Hop is this: during the first stages of development, what is observed is that the Hop interaction is one which results in a cessation of the differentiation processes which are induced by SRF. In the later stages, it appears that Hop reduces cell proliferation which is normally caused by SRF.Physiological126153012297045Chen F, Kook H, Milewski R, Gitler AD, Lu MM, Li J, Nazarian R, Schnepp R, Jen K, Biben C, Runke G, Mackay JP, Novotny J, Schwartz RJ, Harvey RP, Mullins MC, Epstein JA: Hop is an unusual homeobox gene that modulates cardiac development. Cell. 2002 Sep 20;110(6):713-23.91783Pathway26153111038368Moore ML, Wang GL, Belaguli NS, Schwartz RJ, McMillin JB: GATA-4 and serum response factor regulate transcription of the muscle-specific carnitine palmitoyltransferase I beta in rat heart. J Biol Chem. 2001 Jan 12;276(2):1026-33. doi: 10.1074/jbc.M009352200.91783Pathway2615329584181Sepulveda JL, Belaguli N, Nigam V, Chen CY, Nemer M, Schwartz RJ: GATA-4 and Nkx-2.5 coactivate Nkx-2 DNA binding targets: role for regulating early cardiac gene expression. Mol Cell Biol. 1998 Jun;18(6):3405-15.91783Pathway26153311983708Sepulveda JL, Vlahopoulos S, Iyer D, Belaguli N, Schwartz RJ: Combinatorial expression of GATA4, Nkx2-5, and serum response factor directs early cardiac gene activity. J Biol Chem. 2002 Jul 12;277(28):25775-82. doi: 10.1074/jbc.M203122200. Epub 2002 Apr 30.91783Pathway1CellCL:00000001Homo sapiens9606EukaryoteHuman5CytoplasmGO:000573715NucleusGO:00056348511PW_BS000008231511PW_BS00002327151PW_BS000027127PW_B00012733110381ProteinComplex13327532ProteinComplex1128PW_B0001283337532ProteinComplex133410382ProteinComplex133510383ProteinComplex18746Serum response factorP11831
SRF is a transcription factor that binds to the serum response element (SRE), a short sequence of dyad symmetry located 300 bp to the 5' of the site of transcription initiation of some genes (such as FOS). Required for cardiac differentiation and maturation.
SRF180086880958231315742717978Homeodomain-only proteinQ9BPY8
Atypical homeodomain protein which does not bind DNA and is required to modulate cardiac growth and development. Acts via its interaction with SRF, thereby modulating the expression of SRF-dependent cardiac-specific genes and cardiac development. Prevents SRF-dependent transcription either by inhibiting SRF binding to DNA or by recruiting histone deacetylase (HDAC) proteins that prevent transcription by SRF. Overexpression causes cardiac hypertrophy (By similarity). May act as a tumor suppressor. Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and assists in chaperone-mediated protein refolding (PubMed:27708256).
HOPX113157281315732717979Transcription factor GATA-4P43694
Transcriptional activator that binds to the consensus sequence 5'-AGATAG-3' and plays a key role in cardiac development and function (PubMed:24000169, PubMed:27984724). In cooperation with TBX5, it binds to cardiac super-enhancers and promotes cardiomyocyte gene expression, while it downregulates endocardial and endothelial gene expression (PubMed:27984724). Involved in bone morphogenetic protein (BMP)-mediated induction of cardiac-specific gene expression. Binds to BMP response element (BMPRE) DNA sequences within cardiac activating regions (By similarity). Acts as a transcriptional activator of ANF in cooperation with NKX2-5 (By similarity). Promotes cardiac myocyte enlargement (PubMed:20081228). Required during testicular development (PubMed:21220346). May play a role in sphingolipid signaling by regulating the expression of sphingosine-1-phosphate degrading enzyme, spingosine-1-phosphate lyase (PubMed:15734735).
GATA411315752717980Homeobox protein Nkx-2.5P52952
Implicated in commitment to and/or differentiation of the myocardial lineage. Acts as a transcriptional activator of ANF in cooperation with GATA4 (By similarity). Binds to the core DNA motif of NPPA promoter (PubMed:22849347, PubMed:26926761). It is transcriptionally controlled by PBX1 and acts as a transcriptional repressor of CDKN2B (By similarity). It is required for spleen development.
NKX2-511315762710381Homeodomain-only protein1PW_P01038118766179787532Serum response factor1PW_P007532154088746800762310382Transcription factor GATA-41PW_P010382187671797910383Homeobox protein Nkx-2.51PW_P01038318768179801018ActivationPW_I00101820357532ProteinComplex12036127Bound11019ActivationPW_I001019203710381ProteinComplex12038127Bound11020ActivationPW_I00102020397532ProteinComplex12040128Bound11021ActivationPW_I001021204110382ProteinComplex12042128Bound11022ActivationPW_I001022204310383ProteinComplex12044128Bound11023ActivationPW_I0010232045128Bound12046128Bound15411272791655902654490297295690365449129729575421282791655904654508297303590565450929730369066545102973037543128279165590765453029731249086545312973125909654532297312676827217978272false15682458subunitregular150707682738746272false15683058subunitregular150707682908746272false12635908subunitregular1507076829117979272false12636558subunitregular1507076829217980272false12637158subunitregular150707683128746272false6585958subunitregular1507076831317979272false6586558subunitregular1507076831417980272false6587158subunitregular150707682718746272false15684608subunitregular1507076827817978272false12632458subunitregular1507076829817979272false15737158subunitregular1507076830217980272false15685908subunitregular15070654490103819165527766636768272654491753291655277666377682736545087532916552776665476829065450910382916552776665576829165451010383916552776665676829265453075329165527766676768312654531103829165527766677768313654532103839165527766678768314654489753291655277666357682716544961038191655277666427682786545161038291655277666627682986545201038391655277666667683022972955M1643 460 C1643 430 958 1075 958 1045 149true182972956M948 855 L948 905 L998 855 z10true182972957M948 915 L948 965 L998 915 z10true182972958M1643 375 C1643 405 1643 430 1643 460 149false18trueM 25.946855044164835 238.26155629629605 L 11 237 L 17.380887721185843 250.57513432307834false2972980M1413 280 C1443 280 848 925 878 925 149true182972981M1568 280 C1538 280 1443 280 1413 280 149false18trueM 568.9468550441649 674.261556296296 L 554 673 L 560.3808877211858 686.5751343230784false2973034M1643 530 C1643 560 1288 1225 1288 1255 149true182973035M1103 1295 L1103 1345 L1153 1295 z10true182973036M1103 1355 L1103 1405 L1153 1355 z10true182973037M1103 1415 L1103 1465 L1153 1415 z10true182973038M1338 590 C1338 560 1337 526 1337 496 C1359 496 1544 495 1568 495 149false18trueM 568.9468550441649 674.261556296296 L 554 673 L 560.3808877211858 686.5751343230784false2973064M1568 625 C1538 625 1363 1395 1333 1395 149true182973065M1413 625 C1443 625 1538 625 1568 625 149false18trueM 1697.9903810567666 1452.5 L 1685 1460 L 1697.9903810567666 1467.5false2973078M1568 625 C1538 625 1348 1365 1318 1365 149true182973079M1413 750 C1443 750 1543 750 1573 750 149false18trueM 568.9468550441649 674.261556296296 L 554 673 L 560.3808877211858 686.5751343230784false2973123M1263 750 C1233 750 1063 1395 1033 1395 149true182973124M111 1987 L111 2037 L161 1987 z10true182973125M111 2047 L111 2097 L161 2047 z10true182973126M111 2107 L111 2157 L161 2107 z10true182973127M808 750 C838 750 1233 750 1263 750 149false18trueM 568.9468550441649 674.261556296296 L 554 673 L 560.3808877211858 686.5751343230784false2973167M907 272 C885 271 753 273 733 272 C733 372 734 570 733 595 149false18trueM 1166.3810608861127 1050.109400448862 L 1179 1042 L 1165.6675836448808 1035.1263783829954false2521101891655276635412972958Right31116544892972955Left2522101991655276645412972981Right31126544962972980Left2523102091655276655422973038Right31136544892973034Left2524102191655276665422973065Right31146545162973064Left2525102291655276675422973079Right31156545202973078Left2526102391655276685422973123Left6695432973127Right6404429731671486081716150.90.902143272671486278712560.20.29075430001764304274M125 225 C125 175 175 125 225 125 C688 125 1289 125 1752 125 C1802 125 1852 175 1852 225 C1852 413 1852 657 1852 845 C1852 895 1802 945 1752 945 C1289 945 688 945 225 945 C175 945 125 895 125 845 C125 657 125 413 125 225 1true61727.0820.036187215Cardiomyocyte Differentiation911206201.61.616015361876235Nucleus913417201.61.620015361877235Cytoplasm166187201.31.320015145185355747507196178086739#FFF9C941273671