title: Hunk/Mak-v is a negative regulator of intestinal cell proliferation.
abstract: 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.
authors.affiliation: University of Cardiff, European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff, CF10 3AX, UK. Reedkr@cf.ac.uk.
authors.forename: Karen R
authors.initials: KR
authors.lastname: Reed
authors.affiliation: School of Biosciences, University of Cardiff, Cardiff, CF10 3AX, UK. igorvk@igb.ac.ru.|Russian Academy of Sciences, Institute of Gene Biology, 34/5 Vavilov street, Moscow, 119334, Russia Federation. igorvk@igb.ac.ru.
authors.forename: Igor V
authors.initials: IV
authors.lastname: Korobko
authors.affiliation: School of Biosciences, University of Cardiff, Cardiff, CF10 3AX, UK. NinkinaN@cardiff.ac.uk.|Institute of General Pathology and Pathophysiology of Russian Academy of Medical Science, 8 Baltijskaya str, Moscow, 125315, Russian Federation. NinkinaN@cardiff.ac.uk.
authors.forename: Natalia
authors.initials: N
authors.lastname: Ninkina
authors.affiliation: Russian Academy of Sciences, Institute of Gene Biology, 34/5 Vavilov street, Moscow, 119334, Russia Federation. alenavk@igb.ac.ru.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Korobko
authors.affiliation: School of Biosciences, University of Cardiff, Cardiff, CF10 3AX, UK. benjamin.hopkins@linacre.ox.ac.uk.
authors.forename: Ben R
authors.initials: BR
authors.lastname: Hopkins
authors.affiliation: School of Biosciences, University of Cardiff, Cardiff, CF10 3AX, UK. plattj@well.ox.ac.uk.
authors.forename: James L
authors.initials: JL
authors.lastname: Platt
authors.affiliation: School of Biosciences, University of Cardiff, Cardiff, CF10 3AX, UK. BuchmanVL@cardiff.ac.uk.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Buchman
authors.affiliation: University of Cardiff, European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff, CF10 3AX, UK. clarkear@cf.ac.uk.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D018390:Gene Targeting; D056426:Genetic Loci; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D047368:Tumor Burden; D015854:Up-Regulation; D060449:Wnt Signaling Pathway
chemical_list: D011494:Protein Kinases; C417729:Hunk protein, mouse; D017346:Protein Serine-Threonine Kinases