Kinase Regulation of HOX Transcription Factors

Abstract

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.

Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia

“…In particular, phosphorylation of the S204 residue by PKC strongly decreased HOXA9/DNA and HOXA9/PBX1/DNA complex formation in vitro, and PKC inhibition by bisindolyl-maleamide 1 decreases TPA-induced differentiation in a HOXA9-transformed murine cell line [107] (Figure 3, point t). Many other HOX proteins are also subjected to phosphorylation by PKC, CKII, cyclin-dependent kinase (CDK), MAPK, ATM/ATR, and other kinases as recently reviewed [312], but the precise function of many is still unclear and no therapeutic approaches have yet been developed in clinical trials, even if it has been shown that PKC inhibition by Ro31 enhances the effect of HXR9 peptide on necroptosis [8].…”

<p>MicroRNA-186-5p Inhibits Proliferation And Metastasis Of Esophageal Cancer By Mediating HOXA9</p>

“…Homeobox genes (HOX genes) are an important family of genes regulating embryonic development and cell growth and differentiation in vivo. With the continuous development of the understanding of HOX genes, recent studies have found that HOX genes are closely related to the occurrence, development, invasion and metastasis of tumors 20,21. Studies have shown that HOX gene plays a positive or negative regulatory role in the process of cell proliferation and differentiation, and is closely related to the occurrence and development of gastrointestinal tumors, breast cancer, endometrial cancer, etc 21.…”

“…With the continuous development of the understanding of HOX genes, recent studies have found that HOX genes are closely related to the occurrence, development, invasion and metastasis of tumors 20,21. Studies have shown that HOX gene plays a positive or negative regulatory role in the process of cell proliferation and differentiation, and is closely related to the occurrence and development of gastrointestinal tumors, breast cancer, endometrial cancer, etc 21. As a member of the HOX family, HOXA9 gene may be a new tumor molecular marker protein, which may play an important role in the development of ECa 22,23.…”

Quantitative Analysis of Differential Expression of HOX Genes in Multiple Cancers

“…Multiple reports have demonstrated that mis-regulation of HOX genes expression plays key roles in the development of cancers. Only in the last five years have more than 50 reviews related to this subject been published; see, for example, References [4,[8][9][10][11]. However, such studies were typically based on different technologies used in different labs and analyzed by different computational tools.…”