HHEX explained

Hematopoietically-expressed homeobox protein HHEX is a protein that in humans is encoded by the HHEX gene and also known as Proline Rich Homeodomain protein PRH.^{[1] [2] [3]}

This gene encodes a member of the homeobox family of transcription factors, many of which are involved in developmental processes. Expression in specific hematopoietic lineages suggests that this protein may play a role in hematopoietic differentiation but the expression of this protein is not limited to hematopoietic cells.

Function

The HHEX transcription factor acts as a activator of transcription in some instances and a repressor of transcription others.^{[4] [5]} It interacts with a number of other signaling molecules to play an important role in the development of multiple organs, such as the liver, thyroid and forebrain. HHEX serves to repress VEGFA, another protein which is important in endothelial cell development.^[6] SCL, a significant transcription factor for blood and endothelial cell differentiation, is shown to interact with HHEX to promote the correct development of the hematopoiesis process.^[7] HHEX appears to work together with another molecule, β-catenin, for the development of the anterior organizer.^[8] It also contributes to developmental remodeling and stabilization of endothelial cells in an unborn organism. The importance of this transcription factor is illustrated by the inability of HHEX knockout mice embryos to survive gestation. Without the expression of HHEX, these mice embryos die in utero between Day 13 and Day 16. HHEX knockout mice display a range of abnormalities including forebrain abnormalities in various levels of severity, as well as a number of other defects including heart, vasculature, liver, monocyte, and thyroid abnormalities.^[9] The HHEX protein is important in a variety of cancers and it can act as an tumour suppressor protein or as an oncoprotein depending on the cancer type.

Interactions

HHEX has been shown to interact with Promyelocytic leukemia protein.^[10]

Further reading

• Neidle S, Goodwin GH . A homology-based molecular model of the proline-rich homeodomain protein Prh, from haematopoietic cells . FEBS Letters . 345 . 2–3 . 93–8 . May 1994 . 7911091 . 10.1016/0014-5793(94)00446-3 . 32905277 . free . 1994FEBSL.345...93N .
• Crompton MR, Bartlett TJ, MacGregor AD, Manfioletti G, Buratti E, Giancotti V, Goodwin GH . Identification of a novel vertebrate homeobox gene expressed in haematopoietic cells . Nucleic Acids Research . 20 . 21 . 5661–7 . Nov 1992 . 1360645 . 334400 . 10.1093/nar/20.21.5661 .
• Manfioletti G, Gattei V, Buratti E, Rustighi A, De Iuliis A, Aldinucci D, Goodwin GH, Pinto A . Differential expression of a novel proline-rich homeobox gene (Prh) in human hematolymphopoietic cells . Blood . 85 . 5 . 1237–45 . Mar 1995 . 7858254 . 10.1182/blood.V85.5.1237.bloodjournal8551237.
• Topcu Z, Mack DL, Hromas RA, Borden KL . The promyelocytic leukemia protein PML interacts with the proline-rich homeodomain protein PRH: a RING may link hematopoiesis and growth control . Oncogene . 18 . 50 . 7091–100 . Nov 1999 . 10597310 . 10.1038/sj.onc.1203201 . free .
• Pellizzari L, D'Elia A, Rustighi A, Manfioletti G, Tell G, Damante G . Expression and function of the homeodomain-containing protein Hex in thyroid cells . Nucleic Acids Research . 28 . 13 . 2503–11 . Jul 2000 . 10871399 . 102703 . 10.1093/nar/28.13.2503 .
• Schaefer LK, Wang S, Schaefer TS . Functional interaction of Jun and homeodomain proteins . The Journal of Biological Chemistry . 276 . 46 . 43074–82 . Nov 2001 . 11551904 . 10.1074/jbc.M102552200 . free .
• Morgutti M, Demori E, Pecile V, Amoroso A, Rustighi A, Manfioletti G . Genomic organization and chromosome mapping of the human homeobox gene HHEX . Cytogenetics and Cell Genetics . 94 . 1–2 . 30–2 . 2001 . 11701950 . 10.1159/000048778 . 2024-07-25 . 28072668 .
• D'Elia AV, Tell G, Russo D, Arturi F, Puglisi F, Manfioletti G, Gattei V, Mack DL, Cataldi P, Filetti S, Di Loreto C, Damante G . Expression and localization of the homeodomain-containing protein HEX in human thyroid tumors . The Journal of Clinical Endocrinology and Metabolism . 87 . 3 . 1376–83 . Mar 2002 . 10.1210/jcem.87.3.8344 . 11889211 . free .
• Topisirovic I, Culjkovic B, Cohen N, Perez JM, Skrabanek L, Borden KL . The proline-rich homeodomain protein, PRH, is a tissue-specific inhibitor of eIF4E-dependent cyclin D1 mRNA transport and growth . The EMBO Journal . 22 . 3 . 689–703 . Feb 2003 . 12554669 . 140753 . 10.1093/emboj/cdg069 .
• Nakagawa T, Abe M, Yamazaki T, Miyashita H, Niwa H, Kokubun S, Sato Y . HEX acts as a negative regulator of angiogenesis by modulating the expression of angiogenesis-related gene in endothelial cells in vitro . Arteriosclerosis, Thrombosis, and Vascular Biology . 23 . 2 . 231–7 . Feb 2003 . 12588764 . 10.1161/01.ATV.0000052670.55321.87 . free .
• Puppin C, D'Elia AV, Pellizzari L, Russo D, Arturi F, Presta I, Filetti S, Bogue CW, Denson LA, Damante G . Thyroid-specific transcription factors control Hex promoter activity . Nucleic Acids Research . 31 . 7 . 1845–52 . Apr 2003 . 12655000 . 152810 . 10.1093/nar/gkg295 .
• Bess KL, Swingler TE, Rivett AJ, Gaston K, Jayaraman PS . The transcriptional repressor protein PRH interacts with the proteasome . The Biochemical Journal . 374 . Pt 3 . 667–75 . Sep 2003 . 12826010 . 1223646 . 10.1042/BJ20030769 .
• George A, Morse HC, Justice MJ . The homeobox gene Hex induces T-cell-derived lymphomas when overexpressed in hematopoietic precursor cells . Oncogene . 22 . 43 . 6764–73 . Oct 2003 . 14555989 . 10.1038/sj.onc.1206822 . free .
• Minami T, Murakami T, Horiuchi K, Miura M, Noguchi T, Miyazaki J, Hamakubo T, Aird WC, Kodama T . Interaction between hex and GATA transcription factors in vascular endothelial cells inhibits flk-1/KDR-mediated vascular endothelial growth factor signaling . The Journal of Biological Chemistry . 279 . 20 . 20626–35 . May 2004 . 15016828 . 10.1074/jbc.M308730200 . free .
• Puppin C, Presta I, D'Elia AV, Tell G, Arturi F, Russo D, Filetti S, Damante G . Functional interaction among thyroid-specific transcription factors: Pax8 regulates the activity of Hex promoter . Molecular and Cellular Endocrinology . 214 . 1–2 . 117–25 . Feb 2004 . 15062550 . 10.1016/j.mce.2003.10.061 . 19285619 .
• Swingler TE, Bess KL, Yao J, Stifani S, Jayaraman PS . The proline-rich homeodomain protein recruits members of the Groucho/Transducin-like enhancer of split protein family to co-repress transcription in hematopoietic cells . The Journal of Biological Chemistry . 279 . 33 . 34938–47 . Aug 2004 . 15187083 . 10.1074/jbc.M404488200 . free .

Notes and References

1. Bedford FK, Ashworth A, Enver T, Wiedemann LM . HEX: a novel homeobox gene expressed during haematopoiesis and conserved between mouse and human . Nucleic Acids Research . 21 . 5 . 1245–9 . Mar 1993 . 8096636 . 309289 . 10.1093/nar/21.5.1245 .
2. Hromas R, Radich J, Collins S . PCR cloning of an orphan homeobox gene (PRH) preferentially expressed in myeloid and liver cells . Biochemical and Biophysical Research Communications . 195 . 2 . 976–83 . Sep 1993 . 8103988 . 10.1006/bbrc.1993.2140 .
3. Web site: Entrez Gene: HHEX hematopoietically expressed homeobox.
4. Denson LA, Karpen SJ, Bogue CW, Jacobs HC . Divergent homeobox gene hex regulates promoter of the Na(+)-dependent bile acid cotransporter . American Journal of Physiology. Gastrointestinal and Liver Physiology . 279 . 2 . G347-55 . Aug 2000 . 10915644 . 10.1152/ajpgi.2000.279.2.G347 . 846822 .
5. Brickman JM, Jones CM, Clements M, Smith JC, Beddington RS . Hex is a transcriptional repressor that contributes to anterior identity and suppresses Spemann organiser function . Development . 127 . 11 . 2303–15 . Jun 2000 . 10.1242/dev.127.11.2303 . 10804173 .
6. Hallaq H, Pinter E, Enciso J, McGrath J, Zeiss C, Brueckner M, Madri J, Jacobs HC, Wilson CM, Vasavada H, Jiang X, Bogue CW . A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels . Development . 131 . 20 . 5197–209 . Oct 2004 . 15459110 . 10.1242/dev.01393 . free .
7. Liao W, Ho CY, Yan YL, Postlethwait J, Stainier DY . Hhex and scl function in parallel to regulate early endothelial and blood differentiation in zebrafish . Development . 127 . 20 . 4303–13 . Oct 2000 . 10.1242/dev.127.20.4303 . 11003831 .
8. Zamparini AL, Watts T, Gardner CE, Tomlinson SR, Johnston GI, Brickman JM . Hex acts with beta-catenin to regulate anteroposterior patterning via a Groucho-related co-repressor and Nodal . Development . 133 . 18 . 3709–22 . Sep 2006 . 16936074 . 10.1242/dev.02516 . free . 20.500.11820/cbce62f2-beb7-469b-87d6-f943e3c9429e . free .
9. Martinez Barbera JP, Clements M, Thomas P, Rodriguez T, Meloy D, Kioussis D, Beddington RS . The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation . Development . 127 . 11 . 2433–45 . Jun 2000 . 10.1242/dev.127.11.2433 . 10804184 .
10. Topcu Z, Mack DL, Hromas RA, Borden KL . The promyelocytic leukemia protein PML interacts with the proline-rich homeodomain protein PRH: a RING may link hematopoiesis and growth control . Oncogene . 18 . 50 . 7091–100 . Nov 1999 . 10597310 . 10.1038/sj.onc.1203201 . free .