HAND2
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| Location (UCSC) | Chr 4: 173.52 – 173.53 Mb | Chr 8: 57.77 – 57.78 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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Heart- and neural crest derivatives-expressed protein 2 is a protein that in humans is encoded by the HAND2 gene.[5][6]
Function
The protein encoded by this gene belongs to the
Hand2 also plays a critical role in the establishment of a proper implantation environment for pregnancy in mice and humans. The induction of Hand2 by
In addition, Hand2 also plays a role in lower jaw formation and tongue morphogenesis in mice by suppressing the homeobox genes Dlx5 and Dlx6.[11]
It has been recently suggested based on in vitro studies that HAND2 and its associated antisense long noncoding RNA HAND2-AS1 (partially overlapping HAND2 first exon and regulatory promotor region), may have an essential role in fine-tuning mesenchymal-to-epithelial/endothelial (MET) plasticity.[12] In that study basal expression levels of HAND2 were necessary to maintain human mesenchymal stem cell identity, high expression levels were associated with MET towards an endothelial phenotype, and complete knockout (KO) resulted in a senescent-like hypertrophic and cell-cycle arrested phenotypes. That same study also demonstrated by data mining and bioinformatic analyses the preservation of basal human HAND2/HAND2-AS1 expression levels across many different tissues, during embryonic development and in normal homeostatic adult tissue samples. They further demonstrated that deviation from those basal expression levels (up or down regulation) is associated with a long list of pathologies including many different metastasizing cancer types, which may be explained, at least in part by the speculative role of HAND2/HAND2-AS1 in regulation of MET states. Nevertheless, additional studies are required to further elucidate the involvement of HAND2/HAND2-AS1 in these processes, which may represent a promising therapeutic target for many related pathologies.
Interactions
HAND2 has been shown to
Clinical significance
Hand2 interactions with
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 premalignant 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.[16]
Regulation of Hand2
HAND2 is an important transcription factor in development of the endothelial to mesenchymal transition (EMT) which allows for the development of the cardiac cushion in the atrioventricular canal which forms the mitral and tricuspid valves. The Hand2 gene regulatory network contains many genes that function in the EMT process, most notably Snail1, whose expression is lost if Hand2 is deficient. Since HAND2 is essential for separation of the atria and ventricles, a mutation in this gene has been linked to ventricular septal defects. Deficiency in HAND2 is only partially replaced by SNAIL1.[17] The expression of Hand2 is regulated by an upstream long non-coding RNA called Upperhand (Uph) that is needed for RNA polymerase II to transcribe Hand2. If Uph is not present, then there is a decrease in the expression of Hand2 and thus a decrease in cardiac development. When Uph was knocked out, the right ventricular chamber did not develop and had a similar phenotype as when Hand2 is knocked out. In addition, Hand2 expression was absent in the atria, ventricles, and outflow tract of the heart and was reduced in the brachial arches and limb buds.[18]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000164107 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000038193 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 9878849.
- ^ a b "Entrez Gene: HAND2 heart and neural crest derivatives expressed 2".
- ^ PMID 26676105.
- ^ PMID 20819618.)
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- PMID 21558373.
- PMID 38003736.
- PMID 11994297.
- PMID 14636580.
- PMID 14506227.
- PMID 24265601.
- PMID 28538179.
- PMID 27783597.
Further reading
- Srivastava D (1999). "HAND proteins: molecular mediators of cardiac development and congenital heart disease". Trends in Cardiovascular Medicine. 9 (1–2): 11–8. PMID 10189962.
- Firulli AB, McFadden DG, Lin Q, Srivastava D, Olson EN (March 1998). "Heart and extra-embryonic mesodermal defects in mouse embryos lacking the bHLH transcription factor Hand1". Nature Genetics. 18 (3): 266–70. S2CID 36413867.
- Firulli BA, Hadzic DB, McDaid JR, Firulli AB (October 2000). "The basic helix-loop-helix transcription factors dHAND and eHAND exhibit dimerization characteristics that suggest complex regulation of function". The Journal of Biological Chemistry. 275 (43): 33567–73. PMID 10924525.
- McFadden DG, Charité J, Richardson JA, Srivastava D, Firulli AB, Olson EN (December 2000). "A GATA-dependent right ventricular enhancer controls dHAND transcription in the developing heart". Development. 127 (24): 5331–41. PMID 11076755.
- Dai YS, Cserjesi P (April 2002). "The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer". The Journal of Biological Chemistry. 277 (15): 12604–12. PMID 11812799.
- Dai YS, Cserjesi P, Markham BE, Molkentin JD (July 2002). "The transcription factors GATA4 and dHAND physically interact to synergistically activate cardiac gene expression through a p300-dependent mechanism". The Journal of Biological Chemistry. 277 (27): 24390–8. PMID 11994297.
- Srivastava D, Gottlieb PD, Olson EN (2003). "Molecular mechanisms of ventricular hypoplasia". Cold Spring Harbor Symposia on Quantitative Biology. 67: 121–5. PMID 12858532.
- Rychlik JL, Gerbasi V, Lewis EJ (December 2003). "The interaction between dHAND and Arix at the dopamine beta-hydroxylase promoter region is independent of direct dHAND binding to DNA". The Journal of Biological Chemistry. 278 (49): 49652–60. PMID 14506227.
- Firulli BA, Howard MJ, McDaid JR, McIlreavey L, Dionne KM, Centonze VE, Cserjesi P, Virshup DM, Firulli AB (November 2003). "PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation". Molecular Cell. 12 (5): 1225–37. PMID 14636580.
- Murakami M, Kataoka K, Tominaga J, Nakagawa O, Kurihara H (October 2004). "Differential cooperation between dHAND and three different E-proteins". Biochemical and Biophysical Research Communications. 323 (1): 168–74. 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". Journal of Molecular Neuroscience. 27 (3): 281–92. S2CID 1021814.
- Han Z, Yi P, Li X, Olson EN (March 2006). "Hand, an evolutionarily conserved bHLH transcription factor required for Drosophila cardiogenesis and hematopoiesis". Development. 133 (6): 1175–82. PMID 16467358.
External links
- HAND2+protein,+human at the U.S. 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.