{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:54:14Z","timestamp":1790841254841,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,4,10]],"date-time":"2019-04-10T00:00:00Z","timestamp":1554854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The HOX genes are a group of homeodomain-containing transcription factors that play important regulatory roles in early development, including the establishment of cell and tissue identity. HOX expression is generally reduced in adult cells but is frequently re-established as an early event in tumour formation and supports an oncogenic phenotype. HOX transcription factors are also involved in cell cycle regulation and DNA repair, along with normal adult physiological process including stem cell renewal. There have been extensive studies on the mechanism by which HOX proteins regulate transcription, with particular emphasis on their interaction with cofactors such as Pre-B-cell Leukaemia Homeobox (PBX) and Myeloid Ecotropic Viral Integration Site 1 (MEIS). However, significantly less is known of how the activity of HOX proteins is regulated. There is growing evidence that phosphorylation may play an important role in this context, and in this review, we draw together a number of important studies published over the last 20 years, and discuss the relevance of phosphorylation in the regulation and function of HOX proteins in development, evolution, cell cycle regulation, and cancer.<\/jats:p>","DOI":"10.3390\/cancers11040508","type":"journal-article","created":{"date-parts":[[2019,4,10]],"date-time":"2019-04-10T11:25:08Z","timestamp":1554895508000},"page":"508","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Kinase Regulation of HOX Transcription Factors"],"prefix":"10.3390","volume":"11","author":[{"given":"Monika","family":"Primon","sequence":"first","affiliation":[{"name":"Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7873-0877","authenticated-orcid":false,"given":"Keith D.","family":"Hunter","sequence":"additional","affiliation":[{"name":"Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield S10 2TN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hardev S.","family":"Pandha","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8721-4479","authenticated-orcid":false,"given":"Richard","family":"Morgan","sequence":"additional","affiliation":[{"name":"Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ydbio.2010.04.024","article-title":"Hox genes and regional patterning of the vertebrate body plan","volume":"344","author":"Mallo","year":"2010","journal-title":"Dev. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Holland, P.W., Booth, H.A., and Bruford, E.A. (2007). Classification and nomenclature of all human homeobox genes. BMC Biol., 5.","DOI":"10.1186\/1741-7007-5-47"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1016\/j.exphem.2010.07.006","article-title":"HoxA cluster is haploinsufficient for activity of hematopoietic stem and progenitor cells","volume":"38","author":"Fournier","year":"2010","journal-title":"Exp. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1093\/humrep\/deu004","article-title":"Regulation of endometrial receptivity by the highly expressed HOXA9, HOXA11 and HOXD10 HOX-class homeobox genes","volume":"29","author":"Xu","year":"2014","journal-title":"Hum. Reprod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1002\/dvdy.24016","article-title":"Biochemistry of the tale transcription factors PREP, MEIS, and PBX in vertebrates","volume":"243","author":"Longobardi","year":"2014","journal-title":"Dev. Dyn."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s10456-005-9016-7","article-title":"Pbx1 is required for Hox D3-mediated angiogenesis","volume":"8","author":"Charboneau","year":"2005","journal-title":"Angiogenesis"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7509","DOI":"10.1128\/MCB.21.21.7509-7522.2001","article-title":"The HOX homeodomain proteins block CBP histone acetyltransferase activity","volume":"21","author":"Shen","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"707260","DOI":"10.1155\/2012\/707260","article-title":"HOX Gene Aberrant Expression in Skin Melanoma: A Review","volume":"2012","author":"Pierard","year":"2012","journal-title":"J. Skin Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/jop.12388","article-title":"The role of HOX genes in head and neck squamous cell carcinoma","volume":"45","author":"Platais","year":"2016","journal-title":"J. Oral Pathol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/bju.12269","article-title":"Importance of HOX genes in normal prostate gland formation, prostate cancer development and its early detection","volume":"113","author":"Javed","year":"2014","journal-title":"BJU Int."},{"key":"ref_11","first-page":"105","article-title":"HOX genes: Major actors in resistance to selective endocrine response modifiers","volume":"1865","author":"Jin","year":"2016","journal-title":"Biochim. Biophys Acta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1757-2215-4-16","article-title":"HOX genes in ovarian cancer","volume":"4","author":"Kelly","year":"2011","journal-title":"J. Ovarian Res."},{"key":"ref_13","first-page":"216","article-title":"HOX genes in pancreatic development and cancer","volume":"12","author":"Gray","year":"2011","journal-title":"JOP"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5806","DOI":"10.1158\/0008-5472.CAN-06-4231","article-title":"Antagonism of HOX\/PBX dimer formation blocks the in vivo proliferation of melanoma","volume":"67","author":"Morgan","year":"2007","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"457","DOI":"10.4161\/cam.22164","article-title":"The dual roles of homeobox genes in vascularization and wound healing","volume":"6","author":"Kachgal","year":"2012","journal-title":"Cell Adh. Migr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1042\/BJ20150213","article-title":"HOXB5 induces invasion and migration through direct transcriptional up-regulation of beta-catenin in human gastric carcinoma","volume":"472","author":"Hong","year":"2015","journal-title":"Biochem. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6861","DOI":"10.3892\/mmr.2015.4331","article-title":"Knockdown of homeobox A5 by small hairpin RNA inhibits proliferation and enhances cytarabine chemosensitivity of acute myeloid leukemia cells","volume":"12","author":"Li","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1016\/j.ejca.2014.01.024","article-title":"Downregulation of HOXA1 gene affects small cell lung cancer cell survival and chemoresistance under the regulation of miR-100","volume":"50","author":"Xiao","year":"2014","journal-title":"Eur. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1158\/0008-5472.CAN-06-4283","article-title":"A role for the HOXB7 homeodomain protein in DNA repair","volume":"67","author":"Rubin","year":"2007","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Morgan, R., El-Tanani, M., Hunter, K.D., Harrington, K.J., and Pandha, H.S. (2017). Targeting HOX\/PBX dimers in cancer. Oncotarget.","DOI":"10.18632\/oncotarget.15971"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1387\/ijdb.180178rr","article-title":"Post-translational modifications of HOX proteins, an underestimated issue","volume":"62","author":"Draime","year":"2018","journal-title":"Int. J. Dev. Biol"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1038\/nature717","article-title":"Evolution of a transcriptional repression domain in an insect Hox protein","volume":"415","author":"Galant","year":"2002","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s00427-008-0224-1","article-title":"Context-dependent regulation of Hox protein functions by CK2 phosphorylation sites","volume":"218","author":"Hsia","year":"2008","journal-title":"Dev. Genes Evol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11130","DOI":"10.1074\/jbc.270.19.11130","article-title":"Phosphorylation of the Drosophila engrailed protein at a site outside its homeodomain enhances DNA binding","volume":"270","author":"Bourbon","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1101\/gad.11.10.1327","article-title":"A role for phosphorylation by casein kinase II in modulating Antennapedia activity in Drosophila","volume":"11","author":"Jaffe","year":"1997","journal-title":"Genes Dev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5058","DOI":"10.4049\/jimmunol.166.8.5058","article-title":"Identification of novel functional regions important for the activity of HOXB7 in mammalian cells","volume":"166","author":"Yaron","year":"2001","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3247","DOI":"10.1038\/sj.onc.1204411","article-title":"Protein kinase CK2 in mammary gland tumorigenesis","volume":"20","author":"Song","year":"2001","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/0952-7915(95)80075-1","article-title":"New models of lymphoma in transgenic mice","volume":"7","author":"Seldin","year":"1995","journal-title":"Curr. Opin. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ortega, C.E., Seidner, Y., and Dominguez, I. (2014). Mining CK2 in cancer. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115609"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2946","DOI":"10.1093\/emboj\/19.12.2946","article-title":"Phosphorylation status of the SCR homeodomain determines its functional activity: essential role for protein phosphatase 2A,B\u2019","volume":"19","author":"Berry","year":"2000","journal-title":"EMBO J."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Pinto, P.B., Espinosa-Vazquez, J.M., Rivas, M.L., and Hombria, J.C. (2015). JAK\/STAT and Hox Dynamic Interactions in an Organogenetic Gene Cascade. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005412"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3667","DOI":"10.1242\/dev.125.18.3667","article-title":"The beta-catenin homolog BAR-1 and LET-60 Ras coordinately regulate the Hox gene lin-39 during Caenorhabditis elegans vulval development","volume":"125","author":"Eisenmann","year":"1998","journal-title":"Development"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/0092-8674(93)90293-Y","article-title":"Control of cell fates in the central body region of C. elegans by the homeobox gene lin-39","volume":"74","author":"Clark","year":"1993","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8931","DOI":"10.1073\/pnas.1200874109","article-title":"Structural basis for homeodomain recognition by the cell-cycle regulator Geminin","volume":"109","author":"Zhou","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/S0960-9822(06)00157-6","article-title":"Systematic identification of mitotic phosphoproteins","volume":"7","author":"Stukenberg","year":"1997","journal-title":"Curr. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3715","DOI":"10.1093\/emboj\/cdg340","article-title":"Early mitotic degradation of the homeoprotein HOXC10 is potentially linked to cell cycle progression","volume":"22","author":"Gabellini","year":"2003","journal-title":"EMBO J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"210","DOI":"10.20892\/j.issn.2095-3941.2018.0022","article-title":"ATM in breast and brain tumors: a comprehensive review","volume":"15","author":"Estiar","year":"2018","journal-title":"Cancer Biol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.molcel.2017.05.015","article-title":"ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response","volume":"66","author":"Blackford","year":"2017","journal-title":"Mol. Cell."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kang, U.B., Alexander, W.M., and Marto, J.A. (2017). Interrogating the hidden phosphoproteome. Proteomics, 17.","DOI":"10.1002\/pmic.201600437"},{"key":"ref_40","first-page":"843","article-title":"Targeting protein kinase A in cancer therapy: an update","volume":"13","author":"Sapio","year":"2014","journal-title":"EXCLI J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"18904","DOI":"10.1074\/jbc.M109.005090","article-title":"Transcriptional activation by MEIS1A in response to protein kinase A signaling requires the transducers of regulated CREB family of CREB co-activators","volume":"284","author":"Goh","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.mod.2010.08.001","article-title":"Identification of genes downstream of the Shh signalling in the developing chick wing and syn-expressed with Hoxd13 using microarray and 3D computational analysis","volume":"127","author":"Bangs","year":"2010","journal-title":"Mech. Dev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"89566","DOI":"10.18632\/oncotarget.20023","article-title":"Inhibition of HOX\/PBX dimer formation leads to necroptosis in acute myeloid leukemia cells","volume":"8","author":"Alharbi","year":"2017","journal-title":"Oncotarget"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3827","DOI":"10.1128\/MCB.24.9.3827-3837.2004","article-title":"Protein kinase C-mediated phosphorylation of the leukemia-associated HOXA9 protein impairs its DNA binding ability and induces myeloid differentiation","volume":"24","author":"Vijapurkar","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"23","DOI":"10.31557\/APJCP.2019.20.1.23","article-title":"Protein Kinase CK2, a Potential Therapeutic Target in Carcinoma Management","volume":"20","author":"Lian","year":"2019","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1038\/leu.2012.356","article-title":"The role of HOX genes in normal hematopoiesis and acute leukemia","volume":"27","author":"Alharbi","year":"2013","journal-title":"Leukemia"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.4161\/cc.10.9.15494","article-title":"RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesis","volume":"10","author":"Funasaka","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1038\/leu.2017.194","article-title":"The molecular pathogenesis of the NUP98-HOXA9 fusion protein in acute myeloid leukemia","volume":"31","author":"Munoz","year":"2017","journal-title":"Leukemia"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1002\/jcb.23090","article-title":"Targeting PKC-mediated signal transduction pathways using enzastaurin to promote apoptosis in acute myeloid leukemia-derived cell lines and blast cells","volume":"112","author":"Ruvolo","year":"2011","journal-title":"J. Cell. Biochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3389\/fphar.2015.00070","article-title":"The casein kinase 2 inhibitor, CX-4945, as an anti-cancer drug in treatment of human hematological malignancies","volume":"6","author":"Chon","year":"2015","journal-title":"Front. Pharmacol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/4\/508\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:44:21Z","timestamp":1760186661000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/4\/508"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,10]]},"references-count":50,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["cancers11040508"],"URL":"https:\/\/doi.org\/10.3390\/cancers11040508","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,10]]}}}