Journal Article

Hunk/Mak-v is a negative regulator of intestinal cell proliferation

Reed, Karen R, Hopkins, Ben R, Clarke, Alan R, Ninkina, Natalia, Korobko, Igor V, Korobko, Elena V, Platt, James L, Buchman, Vladimir

2015

Overview

Background Conditional deletion of the tumour suppressor gene Apc within the murine intestine results in acute Wnt signalling activation. The associated over-expression of a myriad of Wnt signalling target genes yields phenotypic alterations that encompass many of the hallmarks of neoplasia. Previous transcriptomic analysis aimed at identifying genes that potentially play an important role in this process, inferred the Hormonally upregulated Neu-associated kinase ( HUNK/Mak-v/Bstk1 ) gene as a possible candidate. Hunk is a SNF1 (sucrose non fermenting 1)-related serine/threonine kinase with a proposed association with many different tumour types, including colorectal cancer. Methods Here we describe the generation of a novel Hunk kinase deficient mouse which has been used to investigate the involvement of Hunk-kinase activity in intestinal homeostasis and tumourigenesis. Results We show that in the morphologically normal intestine, Hunk-kinase negatively regulates epithelial cell proliferation. However, the increase in cell proliferation observed in the Hunk kinase deficient intestine is counteracted by increased cell migration, thereby maintaining intestinal homeostasis. Using qRT-PCR, we further demonstrate that Hunk is significantly over-expressed in Apc deficient / Wnt-signalling activated intestinal tissue. Using the classical intestinal tumourigenesis Apc Min mouse model we show that loss of Hunk-kinase activity significantly reduced tumour initiation rates in the small intestine. However, an accompanying increase in the size of the tumours counteracts the impact this has on overall tumour burden or subsequently survival. Conclusions In the intestinal setting we demonstrate that Hunk has a role in normal intestinal proliferation and homeostasis and, although it does not alter overall survival rates, activity of this kinase does impact on tumour initiation rates during the early stages in tumourigenesis in the small intestine.

• Publisher: BioMed Central,BioMed Central Ltd
• Subject: Amino Acid Sequence / Analysis / Animals / Base Sequence / Biomedical and Life Sciences / Biomedicine / Cancer Research / Care and treatment / Cell and molecular biology / Cell Proliferation / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - metabolism / Colorectal cancer / Diagnosis / Disease Models, Animal / Embryonic Stem Cells - metabolism / Female / Gene Expression Regulation / Gene Knockdown Techniques / Gene Targeting / Genes / Genetic Loci / Health Promotion and Disease Prevention / Intestinal Mucosa - metabolism / Male / Medicine/Public Health / Mice / Molecular Sequence Data / Neoplasms - genetics / Neoplasms - metabolism / Neoplasms - mortality / Neoplasms - pathology / Oncology / Protein Kinases - deficiency / Protein Kinases - genetics / Protein Kinases - metabolism / Research Article / Risk factors / Surgical Oncology / Tumor Burden / Up-Regulation / Wnt Signaling Pathway