Kinase Regulation of HOX Transcription Factors

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2019 Apr 13

PMID 30974835

Citations 11

Authors

Monika Primon

Keith D Hunter

Hardev S Pandha

Richard Morgan

Affiliations

Soon will be listed here.

Abstract

The 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. 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.

Citing Articles

METTL14-mediated m6A modification upregulates HOXB13 expression to activate NF-κB and exacerbate cervical cancer progression.

Li Q, Zhao N, Ding X, Zhao J Mol Cell Oncol. 2024; 11(1):2423986.

PMID: 39534063 PMC: 11556271. DOI: 10.1080/23723556.2024.2423986.

Prolonging somatic cell proliferation through constitutive hox gene expression in C. elegans.

Heinze S, Berger S, Engleitner S, Daube M, Hajnal A Nat Commun. 2023; 14(1):6850.

PMID: 37891160 PMC: 10611754. DOI: 10.1038/s41467-023-42644-1.

HOXA1 participates in VSMC-to-macrophage-like cell transformation via regulation of NF-κB p65 and KLF4: a potential mechanism of atherosclerosis pathogenesis.

Han Z, Hu H, Yin M, Lin Y, Yan Y, Han P Mol Med. 2023; 29(1):104.

PMID: 37528397 PMC: 10394793. DOI: 10.1186/s10020-023-00685-8.

functions as a potential novel oncopromoter in colorectal cancer: a comprehensive analysis of the gene family.

Martinou E, Moller-Levet C, Angelidi A Am J Cancer Res. 2022; 12(2):585-600.

PMID: 35261789 PMC: 8899996.

Downstream of the HOX genes: Explaining conflicting tumour suppressor and oncogenic functions in cancer.

Morgan R, Hunter K, Pandha H Int J Cancer. 2022; 150(12):1919-1932.

PMID: 35080776 PMC: 9304284. DOI: 10.1002/ijc.33949.

References

Berry M, Gehring W . Phosphorylation status of the SCR homeodomain determines its functional activity: essential role for protein phosphatase 2A,B'. EMBO J. 2000; 19(12):2946-57. PMC: 203353. DOI: 10.1093/emboj/19.12.2946. View

Yaron Y, McAdara J, Lynch M, Hughes E, Gasson J . Identification of novel functional regions important for the activity of HOXB7 in mammalian cells. J Immunol. 2001; 166(8):5058-67. DOI: 10.4049/jimmunol.166.8.5058. View

Romieu-Mourez R, Song D, Sonenshein G, Cardiff R, Seldin D . Protein kinase CK2 in mammary gland tumorigenesis. Oncogene. 2001; 20(25):3247-57. DOI: 10.1038/sj.onc.1204411. View

Shen W, Krishnan K, Lawrence H, Largman C . The HOX homeodomain proteins block CBP histone acetyltransferase activity. Mol Cell Biol. 2001; 21(21):7509-22. PMC: 99922. DOI: 10.1128/MCB.21.21.7509-7522.2001. View

Galant R, Carroll S . Evolution of a transcriptional repression domain in an insect Hox protein. Nature. 2002; 415(6874):910-3. DOI: 10.1038/nature717. View

Gabellini D, Colaluca I, Vodermaier H, Biamonti G, Giacca M, Falaschi A . Early mitotic degradation of the homeoprotein HOXC10 is potentially linked to cell cycle progression. EMBO J. 2003; 22(14):3715-24. PMC: 165610. DOI: 10.1093/emboj/cdg340. View

Vijapurkar U, Fischbach N, Shen W, Brandts C, Stokoe D, Lawrence H . Protein kinase C-mediated phosphorylation of the leukemia-associated HOXA9 protein impairs its DNA binding ability and induces myeloid differentiation. Mol Cell Biol. 2004; 24(9):3827-37. PMC: 387750. DOI: 10.1128/MCB.24.9.3827-3837.2004. View

Charboneau A, East L, Mulholland N, Rohde M, Boudreau N . Pbx1 is required for Hox D3-mediated angiogenesis. Angiogenesis. 2005; 8(4):289-96. DOI: 10.1007/s10456-005-9016-7. View

Rubin E, Wu X, Zhu T, Cheung J, Chen H, Lorincz A . A role for the HOXB7 homeodomain protein in DNA repair. Cancer Res. 2007; 67(4):1527-35. DOI: 10.1158/0008-5472.CAN-06-4283. View

10.

Morgan R, Pirard P, Shears L, Sohal J, Pettengell R, Pandha H . Antagonism of HOX/PBX dimer formation blocks the in vivo proliferation of melanoma. Cancer Res. 2007; 67(12):5806-13. DOI: 10.1158/0008-5472.CAN-06-4231. View

11.

Holland P, Booth H, Bruford E . Classification and nomenclature of all human homeobox genes. BMC Biol. 2007; 5:47. PMC: 2211742. DOI: 10.1186/1741-7007-5-47. View

12.

Taghli-Lamallem O, Hsia C, Ronshaugen M, McGinnis W . Context-dependent regulation of Hox protein functions by CK2 phosphorylation sites. Dev Genes Evol. 2008; 218(6):321-32. PMC: 2443945. DOI: 10.1007/s00427-008-0224-1. View

13.

Goh S, Looi Y, Shen H, Fang J, Bodner C, Houle M . Transcriptional activation by MEIS1A in response to protein kinase A signaling requires the transducers of regulated CREB family of CREB co-activators. J Biol Chem. 2009; 284(28):18904-12. PMC: 2707216. DOI: 10.1074/jbc.M109.005090. View

14.

Mallo M, Wellik D, Deschamps J . Hox genes and regional patterning of the vertebrate body plan. Dev Biol. 2010; 344(1):7-15. PMC: 2909379. DOI: 10.1016/j.ydbio.2010.04.024. View

15.

Lebert-Ghali C, Fournier M, Dickson G, Thompson A, Sauvageau G, Bijl J . HoxA cluster is haploinsufficient for activity of hematopoietic stem and progenitor cells. Exp Hematol. 2010; 38(11):1074-1086.e1-5. DOI: 10.1016/j.exphem.2010.07.006. View

16.

Bangs F, Welten M, Davey M, Fisher M, Yin Y, Downie H . Identification of genes downstream of the Shh signalling in the developing chick wing and syn-expressed with Hoxd13 using microarray and 3D computational analysis. Mech Dev. 2010; 127(9-12):428-41. DOI: 10.1016/j.mod.2010.08.001. View

17.

Ruvolo P, Zhou L, Watt J, Ruvolo V, Burks J, Jiffar T . Targeting PKC-mediated signal transduction pathways using enzastaurin to promote apoptosis in acute myeloid leukemia-derived cell lines and blast cells. J Cell Biochem. 2011; 112(6):1696-707. PMC: 3394435. DOI: 10.1002/jcb.23090. View

18.

Funasaka T, Nakano H, Wu Y, Hashizume C, Gu L, Nakamura T . RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesis. Cell Cycle. 2011; 10(9):1456-67. DOI: 10.4161/cc.10.9.15494. View

19.

Gray S, Pandha H, Michael A, Middleton G, Morgan R . HOX genes in pancreatic development and cancer. JOP. 2011; 12(3):216-9. View

20.

Kelly Z, Michael A, Butler-Manuel S, Pandha H, Morgan R . HOX genes in ovarian cancer. J Ovarian Res. 2011; 4:16. PMC: 3179923. DOI: 10.1186/1757-2215-4-16. View