HAND2

HAND2
Identifiers
Aliases	HAND2, DHed, Thing2, bHLHa26, dHand, heart and neural crest derivatives expressed 2
External IDs	MGI: 103580 HomoloGene: 32092 GeneCards: HAND2
Gene ontology Molecular function • DNA binding • sequence-specific DNA binding • RNA polymerase II regulatory region sequence-specific DNA binding • protein homodimerization activity • protein dimerization activity • AT DNA binding • transcription coactivator activity • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding • transcription factor binding • activating transcription factor binding • E-box binding • protein binding • protein heterodimerization activity • transcription regulatory region DNA binding Cellular component • transcription factor complex • protein complex • nuclear chromatin • nucleus Biological process • positive regulation of transcription regulatory region DNA binding • peripheral nervous system neuron development • palate development • apoptotic process involved in heart morphogenesis • noradrenergic neuron differentiation • cell differentiation • mesenchymal cell proliferation • determination of heart left/right asymmetry • regulation of transcription, DNA-templated • sympathetic nervous system development • tongue development • neural crest cell development • cell proliferation involved in outflow tract morphogenesis • adult heart development • cardiac right ventricle formation • thymus development • mesenchyme development • cardiac neural crest cell migration involved in outflow tract morphogenesis • negative regulation of DNA binding • coronary artery morphogenesis • embryonic digit morphogenesis • positive regulation of transcription from RNA polymerase II promoter involved in norepinephrine biosynthetic process • visceral serous pericardium development • heart morphogenesis • negative regulation of apoptotic process • in utero embryonic development • negative regulation of sequence-specific DNA binding transcription factor activity • negative regulation of osteoblast differentiation • transcription, DNA-templated • cardiac neural crest cell development involved in outflow tract morphogenesis • positive regulation of transcription, DNA-templated • heart looping • odontogenesis of dentin-containing tooth • positive regulation of semaphorin-plexin signaling pathway involved in outflow tract morphogenesis • multicellular organism development • negative regulation of cardiac muscle cell apoptotic process • heart development • regulation of secondary heart field cardioblast proliferation • angiogenesis • cartilage morphogenesis • positive regulation of transcription from RNA polymerase II promoter • suckling behavior • regulation of tissue remodeling • negative regulation of gene expression • positive regulation of ERK1 and ERK2 cascade • positive regulation of p38MAPK cascade • positive regulation of cardiac muscle hypertrophy • positive regulation of gene expression • transcription from RNA polymerase II promoter Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	9464	15111
Ensembl	ENSG00000164107	ENSMUSG00000038193
UniProt	P61296	Q61039
RefSeq (mRNA)	NM_021973	NM_010402
RefSeq (protein)	NP_068808.1	NP_034532.3
Location (UCSC)	Chr 4: 173.52 – 173.53 Mb	Chr 8: 57.32 – 57.32 Mb
PubMed search	[1]	[2]
Wikidata

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Heart- and neural crest derivatives-expressed protein 2 is a protein that in humans is encoded by the HAND2 gene.^[3][4]

Function

The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins, which are asymmetrically expressed in the developing ventricular chambers and play an essential role in cardiac morphogenesis. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries, implicating them as mediators of congenital heart disease. In addition, this transcription factor plays an important role in limb and branchial arch development.^[4]

A progesterone-regulated transcription factor regulates stromal-epithelial communication in early pregnancy.^[5]

HAND2 is involved in the development of the tongue.^[6]

Interactions

HAND2 has been shown to interact with GATA4,^[7] PPP2R5D,^[8] PHOX2A.,^[9] TWIST1, and TWIST2.

Clinical Significance

Hand2 interactions with TWIST1 and TWIST2 genes are critical for proper limb development. Recent literature shows over dosage of Hand2 can result in many defects in the limbs, face, heart, and lower lumbar vertebrae. In this instance, trisomy of the hand2 gene can directly cause human congenital heart disease.^[10]

Hand2 gene hypermethylation and epigenetic silencing has also been implicated to increase the development of endometrial cancer. Mounting evidence showing its methylation increased chances of premalignant endometrial lesions. Hand2, in addition to its other functions in the developing heart and limbs, has been found to be an important transcription factor seen in the endometrial stroma. In fact, in mice with the Hand2 gene knocked out, they developed premaligant lesions as they grew older, further providing evidence of its role in endometrial cancer development. These findings have led to Hand2 becoming a potentially promising biomarker for early detection of endometrial cancer and may be used to predict its treatment.^[11]

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. Russell MW, Kemp P, Wang L, Brody LC, Izumo S (Feb 1999). "Molecular cloning of the human HAND2 gene". Biochim Biophys Acta. 1443 (3): 393–9. doi:10.1016/S0167-4781(98)00237-1. PMID 9878849.
4. "Entrez Gene: HAND2 heart and neural crest derivatives expressed 2".
5. Li Q, Kannan A, DeMayo FJ, Lydon JP, Cooke PS, Yamagishi H, Srivastava D, Bagchi MK, Bagchi IC (18 Feb 2011). "The Antiproliferative Action of Progesterone in Uterine Epithelium Is Meditated by Hand2.". Science. 331 (6019): 912–916. doi:10.1126/science.1197454. PMC 3320855. PMID 21330545.
6. Barron F, Woods C, Kuhn K, Bishop J, Howard MJ, Clouthier DE (2011). "Downregulation of Dlx5 and Dlx6 expression by Hand2 is essential for initiation of tongue morphogenesis". Development (Cambridge, England). 138 (11): 2249–59. doi:10.1242/dev.056929. PMC 3091495. PMID 21558373.
7. Dai YS, Cserjesi P, Markham BE, Molkentin JD (Jul 2002). "The transcription factors GATA4 and dHAND physically interact to synergistically activate cardiac gene expression through a p300-dependent mechanism". J. Biol. Chem. 277 (27): 24390–8. doi:10.1074/jbc.M202490200. PMID 11994297.
8. Firulli BA, Howard MJ, McDaid JR, McIlreavey L, Dionne KM, Centonze VE, Cserjesi P, Virshup DM, Firulli AB (Nov 2003). "PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation". Mol. Cell. 12 (5): 1225–37. doi:10.1016/S1097-2765(03)00425-8. PMID 14636580.
9. Rychlik JL, Gerbasi V, Lewis EJ (Dec 2003). "The interaction between dHAND and Arix at the dopamine beta-hydroxylase promoter region is independent of direct dHAND binding to DNA". J. Biol. Chem. 278 (49): 49652–60. doi:10.1074/jbc.M308577200. PMID 14506227.
10. Shen, Lei; Li, Xiao-Feng; Shen, A.-Dong; Wang, Qiang; Liu, Cai-Xia; Guo, Ya-Jie; Song, Zhen-Jiang; Li, Zhong-Zhi (2010-07-01). "Transcription factor HAND2 mutations in sporadic Chinese patients with congenital heart disease". Chinese Medical Journal. 123 (13): 1623–1627. ISSN 0366-6999. PMID 20819618.
11. Jones, Allison; Teschendorff, Andrew E.; Li, Quanxi; Hayward, Jane D.; Kannan, Athilakshmi; Mould, Tim; West, James; Zikan, Michal; Cibula, David (2013-11-01). "Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development". PLoS Medicine. 10 (11): e1001551. doi:10.1371/journal.pmed.1001551. ISSN 1549-1676. PMC 3825654. PMID 24265601.

Further reading

• Srivastava D (1999). "HAND proteins: molecular mediators of cardiac development and congenital heart disease". Trends Cardiovasc. Med. 9 (1–2): 11–8. doi:10.1016/S1050-1738(98)00033-4. PMID 10189962.
• Firulli AB, McFadden DG, Lin Q, Srivastava D, Olson EN (1998). "Heart and extra-embryonic mesodermal defects in mouse embryos lacking the bHLH transcription factor Hand1". Nat. Genet. 18 (3): 266–70. doi:10.1038/ng0398-266. PMID 9500550.
• Firulli BA, Hadzic DB, McDaid JR, Firulli AB (2000). "The basic helix-loop-helix transcription factors dHAND and eHAND exhibit dimerization characteristics that suggest complex regulation of function". J. Biol. Chem. 275 (43): 33567–73. doi:10.1074/jbc.M005888200. PMC 2561327. PMID 10924525.
• McFadden DG, Charité J, Richardson JA, Srivastava D, Firulli AB, Olson EN (2001). "A GATA-dependent right ventricular enhancer controls dHAND transcription in the developing heart". Development. 127 (24): 5331–41. PMID 11076755.
• Dai YS, Cserjesi P (2002). "The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer". J. Biol. Chem. 277 (15): 12604–12. doi:10.1074/jbc.M200283200. PMID 11812799.
• Dai YS, Cserjesi P, Markham BE, Molkentin JD (2002). "The transcription factors GATA4 and dHAND physically interact to synergistically activate cardiac gene expression through a p300-dependent mechanism". J. Biol. Chem. 277 (27): 24390–8. doi:10.1074/jbc.M202490200. PMID 11994297.
• Srivastava D, Gottlieb PD, Olson EN (2003). "Molecular mechanisms of ventricular hypoplasia". Cold Spring Harb. Symp. Quant. Biol. 67: 121–5. doi:10.1101/sqb.2002.67.121. PMID 12858532.
• Rychlik JL, Gerbasi V, Lewis EJ (2004). "The interaction between dHAND and Arix at the dopamine beta-hydroxylase promoter region is independent of direct dHAND binding to DNA". J. Biol. Chem. 278 (49): 49652–60. doi:10.1074/jbc.M308577200. PMID 14506227.
• Firulli BA, Howard MJ, McDaid JR, McIlreavey L, Dionne KM, Centonze VE, Cserjesi P, Virshup DM, Firulli AB (2004). "PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation". Mol. Cell. 12 (5): 1225–37. doi:10.1016/S1097-2765(03)00425-8. PMID 14636580.
• Murakami M, Kataoka K, Tominaga J, Nakagawa O, Kurihara H (2004). "Differential cooperation between dHAND and three different E-proteins". Biochem. Biophys. Res. Commun. 323 (1): 168–74. doi:10.1016/j.bbrc.2004.08.072. PMID 15351717.
• Rychlik JL, Hsieh M, Eiden LE, Lewis EJ (2006). "Phox2 and dHAND transcription factors select shared and unique target genes in the noradrenergic cell type". J. Mol. Neurosci. 27 (3): 281–92. doi:10.1385/JMN:27:3:281. PMID 16280598.
• Han Z, Yi P, Li X, Olson EN (2006). "Hand, an evolutionarily conserved bHLH transcription factor required for Drosophila cardiogenesis and hematopoiesis". Development. 133 (6): 1175–82. doi:10.1242/dev.02285. PMID 16467358.

External links

• HAND2 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.