Developing Practical Therapeutic Strategies that Target Protein SUMOylation

Author(s): Olivia F. Cox , Paul W. Huber* .

Journal Name: Current Drug Targets

Volume 20 , Issue 9 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Post-translational modification by small ubiquitin-like modifier (SUMO) has emerged as a global mechanism for the control and integration of a wide variety of biological processes through the regulation of protein activity, stability and intracellular localization. As SUMOylation is examined in greater detail, it has become clear that the process is at the root of several pathologies including heart, endocrine, and inflammatory disease, and various types of cancer. Moreover, it is certain that perturbation of this process, either globally or of a specific protein, accounts for many instances of congenital birth defects. In order to be successful, practical strategies to ameliorate conditions due to disruptions in this post-translational modification will need to consider the multiple components of the SUMOylation machinery and the extraordinary number of proteins that undergo this modification.

Keywords: SUMO, SUMO ligase, SENP protease, heart development, heart failure, cancer, neurodegenerative disease, congenital birth defects, spina bifida, neural tube.  

[1]
Geiss-Friedlander R, Melchior F. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 2007; 8: 947-56.
[2]
Zhao J. Sumoylation regulates diverse biological processes. Cell Mol Life Sci 2007; 64: 3017-33.
[3]
Gareau JR, Lima CD. The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol 2010; 11: 861-71.
[4]
Saitoh H, Hinchey J. Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem 2000; 275: 6252-8.
[5]
Vertegaal AC, Andersen JS, Ogg SC, Hay RT, Mann M, Lamond AI. Distinct and overlapping sets of SUMO-1 and SUMO-2 target proteins revealed by quantitative proteomics. Mol Cell Proteomics 2006; 5: 2298-310.
[6]
Baczyk D, Audette MC, Drewlo S, Levytska K, Kingdom JC. SUMO-4: A novel functional candidate in the human placental protein SUMOylation machinery. PLoS One 2017; 12: e0178056.
[7]
Cong-Yi W, Jin-Xiong S. SUMO4 and its role in type 1 diabetes pathogenesis. Diabetes Metab Res Rev 2008; 24: 93-102.
[8]
Chen S, Yang T, Liu F, et al. Inflammatory factor-specific sumoylation regulates NF-kB signalling in glomerular cells from diabetic rats. Inflamm Res 2014; 63: 23-31.
[9]
Olsen SK, Capili AD, Lu X, Tan DS, Lima CD. Active site remodeling accompanies thioester bond formation in the SUMO E1. Nature 2010; 463: 906-12.
[10]
Kunz K, Piller T, Muller S. SUMO-specific proteases and isopeptidases of the SENP family at a glance. J Cell Sci 2018; 131.
[11]
Hendriks IA, D’Souza RC, Yang B, et al. Uncovering global SUMOylation signaling networks in a site-specific manner. Nat Struct Mol Biol 2014; 21: 927-36.
[12]
Eifler K, Vertegaal AC. SUMOylation-mediated regulation of cell cycle progression and cancer. Trends Biochem Sci 2015; 40: 779-93.
[13]
Iñiguez-Lluhi JA. SUMO modification and transcriptional regulation. in: wilson vg, editor. sumo regulation of cellular processes: Springer Netherlands 2009; 13-40.
[14]
Ma L, Aslanian A, Sun H, et al. Identification of small ubiquitin-like modifier substrates with diverse functions using the Xenopus egg extract system. Mol Cell Proteomics 2014; 13: 1659-75.
[15]
Malik MQ, Bertke MM, Huber PW. Small ubiquitin-like modifier (SUMO)-mediated repression of the Xenopus oocyte 5 S rRNA genes. J Biol Chem 2014; 289: 35468-81.
[16]
Hay RT. SUMO: a history of modification. Mol Cell 2005; 18: 1-12.
[17]
Hendriks IA, Vertegaal ACO. A comprehensive compilation of SUMO proteomics. Nat Rev Mol Cell Biol 2016; 17: 581-95.
[18]
Hendriks IA, Lyon D, Young C, Jensen LJ, Vertegaal AC, Nielsen ML. Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat Struct Mol Biol 2017; 24: 325-36.
[19]
Karvonen U, Jaaskelainen T, Rytinki M, Kaikkonen S, Palvimo JJ. ZNF451 is a novel PML body- and SUMO-associated transcriptional coregulator. J Mol Biol 2008; 382: 585-600.
[20]
Figueroa-Romero C, Iniguez-Lluhi JA, Stadler J, et al. SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle. FASEB J 2009; 23: 3917-27.
[21]
Vertegaal AC. SUMO chains: polymeric signals. Biochem Soc Trans 2010; 38: 46-9.
[22]
Reverter D, Lima CD. Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex. Nature 2005; 435: 687-92.
[23]
Song J, Zhang Z, Hu W, Chen Y. Small ubiquitin-like modifier (SUMO) recognition of a SUMO binding motif: a reversal of the bound orientation. J Biol Chem 2005; 280: 40122-9.
[24]
Stehmeier P, Muller S. Phospho-regulated SUMO interaction modules connect the SUMO system to CK2 signaling. Mol Cell 2009; 33: 400-9.
[25]
Eifler K, Vertegaal AC. Mapping the SUMOylated landscape. FEBS J 2015; 282: 3669-80.
[26]
Lomeli H, Vazquez M. Emerging roles of the SUMO pathway in development. Cell Mol Life Sci 2011; 68: 4045-64.
[27]
Nacerddine K, Lehembre F, Bhaumik M, et al. The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice. Dev Cell 2005; 9: 769-79.
[28]
Nowak M, Hammerschmidt M. Ubc9 regulates mitosis and cell survival during zebrafish development. Mol Biol Cell 2006; 17: 5324-36.
[29]
Wang L, Wansleeben C, Zhao S, et al. SUMO2 is essential while SUMO3 is dispensable for mouse embryonic development. EMBO Rep 2014; 15: 878-85.
[30]
Evdokimov E, Sharma P, Lockett SJ, Lualdi M, Kuehn MR. Loss of SUMO1 in mice affects RanGAP1 localization and formation of PML nuclear bodies, but is not lethal as it can be compensated by SUMO2 or SUMO3. J Cell Sci 2008; 121: 4106-13.
[31]
Zhang FP, Mikkonen L, Toppari J, et al. Sumo-1 function is dispensable in normal mouse development. Mol Cell Biol 2008; 28: 5381-90.
[32]
Li SJ, Hochstrasser M. A new protease required for cell-cycle progression in yeast. Nature 1999; 398: 246-51.
[33]
Cuijpers SAG, Vertegaal ACO. Guiding mitotic progression by crosstalk between post-translational modifications. Trends Biochem Sci 2018; 43: 251-68.
[34]
Wotton D, Pemberton LF, Merrill-Schools J. SUMO and Chromatin Remodeling. Adv Exp Med Biol 2017; 963: 35-50.
[35]
Cubeñas-Potts C, Matunis MJ. SUMO: a multifaceted modifier of chromatin structure and function. Dev Cell 2013; 24: 1-12.
[36]
Jackson SP, Durocher D. Regulation of DNA damage responses by ubiquitin and SUMO. Mol Cell 2013; 49: 795-807.
[37]
Seeler JS, Dejean A. SUMO and the robustness of cancer. Nat Rev Cancer 2017; 17: 184-97.
[38]
Lee JS, Choi HJ, Baek SH. Sumoylation and Its Contribution to Cancer. Adv Exp Med Biol 2017; 963: 283-98.
[39]
Duprez E, Saurin AJ, Desterro JM, et al. SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisation. J Cell Sci 1999; 112: 381-93.
[40]
Gostissa M, Hengstermann A, Fogal V, et al. Activation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO J 1999; 18: 6462-71.
[41]
Rodriguez MS, Desterro JM, Lain S, et al. SUMO-1 modification activates the transcriptional response of p53. EMBO J 1999; 18: 6455-61.
[42]
Inamura K, Shimoji T, Ninomiya H, et al. A metastatic signature in entire lung adenocarcinomas irrespective of morphological heterogeneity. Hum Pathol 2007; 38: 702-9.
[43]
Liu X, Xu Y, Pang Z, et al. Knockdown of SUMO-activating enzyme subunit 2 (SAE2) suppresses cancer malignancy and enhances chemotherapy sensitivity in small cell lung cancer. J Hematol Oncol 2015; 8: 67.
[44]
Shao DF, Wang XH, Li ZY, et al. High-level SAE2 promotes malignant phenotype and predicts outcome in gastric cancer. Am J Cancer Res 2015; 5: 140-54.
[45]
Hoellein A, Fallahi M, Schoeffmann S, et al. Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma. Blood 2014; 124: 2081-90.
[46]
Chen SF, Gong C, Luo M, et al. Ubc9 expression predicts chemoresistance in breast cancer. Chin J Cancer 2011; 30: 638-44.
[47]
Moschos SJ, Jukic DM, Athanassiou C, et al. Expression analysis of Ubc9, the single small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, in normal and malignant tissues. Hum Pathol 2010; 41: 1286-98.
[48]
Yang W, Wang L, Roehn G, et al. Small ubiquitin-like modifier 1-3 conjugation is activated in human astrocytic brain tumors and is required for glioblastoma cell survival. Cancer Sci 2013; 104: 70-7.
[49]
McDoniels-Silvers AL, Nimri CF, Stoner GD, Lubet RA, You M. Differential gene expression in human lung adenocarcinomas and squamous cell carcinomas. Clin Cancer Res 2002; 8: 1127-38.
[50]
Tomasi ML, Tomasi I, Ramani K, et al. S-adenosyl methionine regulates ubiquitin-conjugating enzyme 9 protein expression and sumoylation in murine liver and human cancers. Hepatology 2012; 56: 982-93.
[51]
Moschos SJ, Smith AP, Mandic M, et al. SAGE and antibody array analysis of melanoma-infiltrated lymph nodes: identification of Ubc9 as an important molecule in advanced-stage melanomas. Oncogene 2007; 26: 4216-25.
[52]
Driscoll JJ, Pelluru D, Lefkimmiatis K, et al. The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome. Blood 2010; 115: 2827-34.
[53]
Wu F, Zhu S, Ding Y, Beck WT, Mo YY. MicroRNA-mediated regulation of Ubc9 expression in cancer cells. Clin Cancer Res 2009; 15: 1550-7.
[54]
Liu B, Tahk S, Yee KM, et al. PIAS1 regulates breast tumorigenesis through selective epigenetic gene silencing. PLoS One 2014; 9: e89464.
[55]
Coppola D, Parikh V, Boulware D, Blanck G. Substantially reduced expression of PIAS1 is associated with colon cancer development. J Cancer Res Clin Oncol 2009; 135: 1287-91.
[56]
Wei J, Costa C, Ding Y, et al. mRNA expression of BRCA1, PIAS1, and PIAS4 and survival after second-line docetaxel in advanced gastric cancer. J Natl Cancer Inst 2011; 103: 1552-6.
[57]
Rabellino A, Carter B, Konstantinidou G, et al. The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA. Cancer Res 2012; 72: 2275-84.
[58]
Li J, Xu Y, Long XD, et al. Cbx4 governs HIF-1alpha to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity. Cancer Cell 2014; 25: 118-31.
[59]
Sun L, Li H, Chen J, et al. PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells. J Cell Sci 2013; 126: 3939-47.
[60]
Chien W, Lee KL, Ding LW, et al. PIAS4 is an activator of hypoxia signalling via VHL suppression during growth of pancreatic cancer cells. Br J Cancer 2013; 109: 1795-804.
[61]
Hoefer J, Schafer G, Klocker H, et al. PIAS1 is increased in human prostate cancer and enhances proliferation through inhibition of p21. Am J Pathol 2012; 180: 2097-107.
[62]
Wang L, Banerjee S. Differential PIAS3 expression in human malignancy. Oncol Rep 2004; 11: 1319-24.
[63]
Yang Y, Xia Z, Wang X, et al. Small-molecule inhibitors targeting protein sumoylation as novel anticancer compounds. Mol Pharmacol 2018; 94: 885-94.
[64]
Licciardello MP, Kubicek S. Pharmacological treats for SUMO addicts. Pharmacol Res 2016; 107: 390-7.
[65]
Schimmel J, Eifler K, Sigurethsson JO, et al. Uncovering SUMOylation dynamics during cell-cycle progression reveals FoxM1 as a key mitotic SUMO target protein. Mol Cell 2014; 53: 1053-66.
[66]
Eifler K, Cuijpers SAG, Willemstein E, et al. SUMO targets the APC/C to regulate transition from metaphase to anaphase. Nat Commun 2018; 9: 1119.
[67]
Sarangi P, Zhao X. SUMO-mediated regulation of DNA damage repair and responses. Trends Biochem Sci 2015; 40: 233-42.
[68]
Bogachek MV, De Andrade JP, Weigel RJ. Regulation of epithelial-mesenchymal transition through SUMOylation of transcription factors. Cancer Res 2015; 75: 11-5.
[69]
Bogachek MV, Chen Y, Kulak MV, et al. Sumoylation pathway is required to maintain the basal breast cancer subtype. Cancer Cell 2014; 25: 748-61.
[70]
Wang CM, Liu R, Wang L, Nascimento L, Brennan VC, Yang WH. SUMOylation of FOXM1B alters its transcriptional activity on regulation of MiR-200 family and JNK1 in MCF7 human breast cancer cells. Int J Mol Sci 2014; 15: 10233-51.
[71]
Bertke MM, Cronin L, Zeng E, Huber PW. A deficiency in SUMOylation activity disrupts multiple pathways leading to neural tube and heart defects in Xenopus embryos. Bio Rxiv 2019; 3: 0
[72]
Hock A, Vousden KH. Regulation of the p53 pathway by ubiquitin and related proteins. Int J Biochem Cell Biol 2010; 42: 1618-21.
[73]
Zhang H, Luo J. SUMO wrestling with Ras. Small GTPases 2016; 7: 39-46.
[74]
Kessler JD, Kahle KT, Sun T, et al. A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Sci 2012; 335: 348-53.
[75]
Licciardello MP, Mullner MK, Durnberger G, et al. NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation. Oncogene 2015; 34: 3780-90.
[76]
Yu B, Swatkoski S, Holly A, et al. Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9. Proc Natl Acad Sci USA 2015; 112: E1724-33.
[77]
Miyauchi Y, Yogosawa S, Honda R, Nishida T, Yasuda H. sumoylation of mdm2 by protein inhibitor of activated stat (pias) and ranbp2 enzymes. J Biol Chem 2002; 277: 50131-6.
[78]
Costa MW, Lee S, Furtado MB, et al. Complex SUMO-1 regulation of cardiac transcription factor Nkx2-5. PLoS One 2011; 6: e24812.
[79]
Wang J, Chen L, Wen S, et al. Defective sumoylation pathway directs congenital heart disease. Birth Defects Res A Clin Mol Teratol 2011; 91: 468-76.
[80]
Wang J, Feng XH, Schwartz RJ. SUMO-1 modification activated GATA4-dependent cardiogenic gene activity. J Biol Chem 2004; 279: 49091-8.
[81]
Wang J, Li A, Wang Z, et al. Myocardin sumoylation transactivates cardiogenic genes in pluripotent 10T1/2 fibroblasts. Mol Cell Biol 2007; 27: 622-32.
[82]
Wang J, Schwartz RJ. Sumoylation and regulation of cardiac gene expression. Circ Res 2010; 107: 19-29.
[83]
Wang J, Zhang H, Iyer D, Feng XH, Schwartz RJ. Regulation of cardiac specific nkx2.5 gene activity by small ubiquitin-like modifier. J Biol Chem 2008; 283: 23235-43.
[84]
Du Y, Liu P, Xu T, et al. Luteolin modulates SERCA2a leading to attenuation of myocardial ischemia/ reperfusion injury via sumoylation at lysine 585 in mice. Cell Physiol Biochem 2018; 45: 883-98.
[85]
Tilemann L, Lee A, Ishikawa K, et al. SUMO-1 gene transfer improves cardiac function in a large-animal model of heart failure. Sci Transl Med 2013; 5: 211ra159.
[86]
Zhang YQ, Sarge KD. Sumoylation regulates lamin A function and is lost in lamin A mutants associated with familial cardiomyopathies. J Cell Biol 2008; 182: 35-9.
[87]
Kho C, Lee A, Jeong D, et al. SUMO1-dependent modulation of SERCA2a in heart failure. Nature 2011; 477: 601-5.
[88]
Lee A, Jeong D, Mitsuyama S, et al. The role of SUMO-1 in cardiac oxidative stress and hypertrophy. Antioxid Redox Signal 2014; 21: 1986-2001.
[89]
Kruse M, Schulze-Bahr E, Corfield V, et al. Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J Clin Invest 2009; 119: 2737-44.
[90]
Kim EY, Zhang Y, Beketaev I, et al. SENP5, a SUMO isopeptidase, induces apoptosis and cardiomyopathy. J Mol Cell Cardiol 2015; 78: 154-64.
[91]
Liu Y, Zhao D, Qiu F, et al. Manipulating PML SUMOylation via silencing ubc9 and rnf4 regulates cardiac fibrosis. Mol Ther 2017; 25: 666-78.
[92]
Gupta MK, McLendon PM, Gulick J, et al. UBC9-Mediated sumoylation favorably impacts cardiac function in compromised hearts. Circ Res 2016; 118: 1894-905.
[93]
Kho C, Lee A, Jeong D, et al. Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure. Nat Commun 2015; 6: 7229.
[94]
Bian C, Xu T, Zhu H, et al. Luteolin inhibits ischemia/reperfusion-induced myocardial injury in rats via downregulation of microrna-208b-3p. PLoS One 2015; 10: e0144877.
[95]
Fang F, Li D, Pan H, et al. Luteolin inhibits apoptosis and improves cardiomyocyte contractile function through the PI3K/Akt pathway in simulated ischemia/reperfusion. Pharmacol 2011; 88: 149-58.
[96]
Anderson DB, Zanella CA, Henley JM, Cimarosti H. Sumoylation: implications for neurodegenerative diseases. In: Wilson VG, editor. SUMO regulation of cellular processes. Cham: Springer International Publishing; 2017. p. 261-81.
[97]
Zhong N, Xu J. Synergistic activation of the human MnSOD promoter by DJ-1 and PGC-1alpha: regulation by SUMOylation and oxidation. Hum Mol Genet 2008; 17: 3357-67.
[98]
Shinbo Y, Niki T, Taira T, et al. Proper SUMO-1 conjugation is essential to DJ-1 to exert its full activities. Cell Death Differ 2006; 13: 96-108.
[99]
Moore DJ, Zhang L, Dawson TM, Dawson VL. A missense mutation (L166P) in DJ-1, linked to familial Parkinson’s disease, confers reduced protein stability and impairs homo-oligomerization. J Neurochem 2003; 87: 1558-67.
[100]
Abeywardana T, Pratt MR. Extent of inhibition of alpha-synuclein aggregation in vitro by SUMOylation is conjugation site- and SUMO isoform-selective. Biochem 2015; 54: 959-61.
[101]
Kim YM, Jang WH, Quezado MM, et al. Proteasome inhibition induces alpha-synuclein SUMOylation and aggregate formation. J Neurol Sci 2011; 307: 157-61.
[102]
Tan EK, Skipper LM. Pathogenic mutations in Parkinson disease. Hum Mutat 2007; 28: 641-53.
[103]
Um JW, Chung KC. Functional modulation of parkin through physical interaction with SUMO-1. J Neurosci Res 2006; 84: 1543-54.
[104]
Vassar R, Bennett BD, Babu-Khan S, et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Sci 1999; 286: 735-41.
[105]
Zhang YQ, Sarge KD. Sumoylation of amyloid precursor protein negatively regulates Abeta aggregate levels. Biochem Biophys Res Commun 2008; 374: 673-8.
[106]
Yun SM, Cho SJ, Song JC, et al. SUMO1 modulates Abeta generation via BACE1 accumulation. Neurobiol Aging 2013; 34: 650-62.
[107]
Dorval V, Fraser PE. Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein. J Biol Chem 2006; 281: 9919-24.
[108]
Luo HB, Xia YY, Shu XJ, et al. SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination. Proc Natl Acad Sci USA 2014; 111: 16586-91.
[109]
Steffan JS, Agrawal N, Pallos J, et al. SUMO modification of Huntingtin and Huntington’s disease pathology. Sci 2004; 304: 100-4.
[110]
Subramaniam S, Sixt KM, Barrow R, Snyder SH. Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Sci 2009; 324: 1327-30.
[111]
Kim EY, Chen L, Ma Y, et al. Enhanced desumoylation in murine hearts by overexpressed SENP2 leads to congenital heart defects and cardiac dysfunction. J Mol Cell Cardiol 2012; 52: 638-49.
[112]
Mendler L, Braun T, Muller S. The Ubiquitin-Like SUMO system and heart function: from development to disease. Circ Res 2016; 118: 132-44.
[113]
Anderson DD, Woeller CF, Stover PJ. Small ubiquitin-like modifier-1 (SUMO-1) modification of thymidylate synthase and dihydrofolate reductase. Clin Chem Lab Med 2007; 45: 1760-3.
[114]
Wen S, Zhu H, Lu W, et al. Planar cell polarity pathway genes and risk for spina bifida. Am J Med Genet A 2010; 152A: 299-304.
[115]
Pauws E, Stanier P. FGF signalling and SUMO modification: new players in the aetiology of cleft lip and/or palate. Trends Genet 2007; 23: 631-40.
[116]
Alkuraya FS, Saadi I, Lund JJ, et al. SUMO1 haploinsufficiency leads to cleft lip and palate. Sci 2006; 313: 1751.
[117]
Kim EY, Chen L, Ma Y, et al. Expression of sumoylation deficient Nkx2.5 mutant in Nkx2.5 haploinsufficient mice leads to congenital heart defects. PLoS One 2011; 6: e20803.
[118]
Matsuzaki K, Minami T, Tojo M, et al. Serum response factor is modulated by the SUMO-1 conjugation system. Biochem Biophys Res Commun 2003; 306: 32-8.
[119]
Grégoire S, Tremblay AM, Xiao L, et al. Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation. J Biol Chem 2006; 281: 4423-33.
[120]
Deng Z, Wan M, Sui G. PIASy-mediated sumoylation of Yin Yang 1 depends on their interaction but not the RING finger. Mol Cell Biol 2007; 27: 3780-92.
[121]
Pan MR, Chang TM, Chang HC, et al. Sumoylation of Prox1 controls its ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells. J Cell Sci 2009; 122: 3358-64.
[122]
Arsenian S, Weinhold B, Oelgeschlager M, Ruther U, Nordheim A. Serum response factor is essential for mesoderm formation during mouse embryogenesis. EMBO J 1998; 17: 6289-99.
[123]
Niu Z, Iyer D, Conway SJ, et al. Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart. Proc Natl Acad Sci USA 2008; 105: 17824. 1789.
[124]
Lyons I, Parsons LM, Hartley L, et al. Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev 1995; 9: 1654-66.
[125]
Khachigian LM. The Yin and Yang of YY1 in tumor growth and suppression. Int J Cancer 2018; 143: 460-5.
[126]
Deng Z, Cao P, Wan MM, Sui G. Yin Yang 1: a multifaceted protein beyond a transcription factor. Transcription 2010; 1: 81-4.
[127]
Gregoire S, Karra R, Passer D, et al. Essential and unexpected role of Yin Yang 1 to promote mesodermal cardiac differentiation. Circ Res 2013; 112: 900-10.
[128]
Crispino JD, Lodish MB, Thurberg BL, et al. Proper coronary vascular development and heart morphogenesis depend on interaction of GATA-4 with FOG cofactors. Genes Dev 2001; 15: 839-44.
[129]
Garg V, Kathiriya IS, Barnes R, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 2003; 424: 443-7.
[130]
Naidu SR, Lakhter AJ, Androphy EJ. PIASy-mediated Tip60 sumoylation regulates p53-induced autophagy. Cell Cycle 2012; 11: 2717-28.
[131]
Yang Y, Fiskus W, Yong B, et al. Acetylated hsp70 and KAP1-mediated Vps34 SUMOylation is required for autophagosome creation in autophagy. Proc Natl Acad Sci USA 2013; 110: 6841-6.
[132]
Mizushima N. Autophagy in protein and organelle turnover. Cold Spring Harb Symp Quant Biol 2011; 76: 397-402.
[133]
Lee E, Koo Y, Ng A, et al. Autophagy is essential for cardiac morphogenesis during vertebrate development. Autophagy 2014; 10: 572-87.
[134]
Terman A, Brunk UT. Autophagy in cardiac myocyte homeostasis, aging, and pathology. Cardiovasc Res 2005; 68: 355-65.
[135]
Nalepa G, Rolfe M, Harper JW. Drug discovery in the ubiquitin-proteasome system. Nat Rev Drug Discov 2006; 5: 596-613.
[136]
Bartlett HL, Sutherland L, Kolker SJ, et al. Transient early embryonic expression of Nkx2-5 mutations linked to congenital heart defects in human causes heart defects in Xenopus laevis. Dev Dyn 2007; 236: 2475-84.
[137]
Knott GJ, Doudna JA. CRISPR-Cas guides the future of genetic engineering. Science 2018; 361: 866-9.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 9
Year: 2019
Page: [960 - 969]
Pages: 10
DOI: 10.2174/1389450119666181026151802

Article Metrics

PDF: 31
HTML: 5