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KLLN (killin, p53-regulated DNA replication inhibitor)

Identity

Other namesCWS4
KILLIN
HGNC (Hugo) KLLN
LocusID (NCBI) 100144748
Location 10q23.31
Location_base_pair Starts at 89618918 and ends at 89623194 bp from pter ( according to hg19-Feb_2009)

DNA/RNA

Description A single exon of 4277 bases.
Transcription KLLN shares a transcription start site with PTEN and is transcribed from the minus strand.
Pseudogene None.

Protein

Note Calculated molecular weight: 19827 Da.
 
  Amino acid sequence.
Description 178 amino acids, DNA binding domain amino acids 8-50.
Localisation Nucleus.
Function KLLN, a target gene of the tumor suppressor p53, is involved in cell cycle arrest and apoptosis (Cho and Liang, 2008). In breast cancer cell lines, KLLN overexpression inhibits cellular proliferation and leads to cell cycle arrest and apoptosis while KLLN knockdown increases cellular proliferation (Wang et al., 2013b). KLLN can bind to DNA and act as a transcription factor; regulating the expression of genes including TP53, TP73, AR and CHK1 (Nizialek et al., 2013 ; Wang et al., 2013b).
Homology None.

Mutations

Germinal 37% of Cowden syndrome patients who were PTEN mutation negative had KLLN promoter hypermethylation which was not seen in controls. Patients with KLLN promoter hypermethylation have an increased risk of breast and renal cancer compared to PTEN mutation positive patients. Methylation leads to a 250-fold decrease in KLLN expression (Bennett et al., 2010).
Germline KLLN promoter methylation has been observed in 56% of patients with apparently sporadic renal cell carcinoma (Bennett et al., 2011).
Germline KLLN mutations have been associated with apparently sporadic breast cancer. 3% of patients with sporadic breast cancer were found to have KLLN mutations while no mutations were observed in controls. Patients with KLLN mutations had a significant family history of breast cancer. These variants were found to dysregulate G2 cell cycle arrest possibly through dysregulated CHK1 expression (Nizialek et al., 2013).
Somatic Somatic KLLN promoter hypermethylation is seen in renal cell carcinoma (Bennett et al., 2011).
Somatic KLLN deletions were observed in 20% of breast carcinomas (Nizialek et al., 2013).

Implicated in

Entity Cowden syndrome
Note Cowden syndome (CS) is an autosomal dominant syndrome and can be attributed to a PTEN mutation in 25% of cases and to KLLN promoter hypermethylation in 37% of PTEN mutation negative CS/CS-like cases. CS is characterized by benign harmatomas as well as malignancies including breast, thyroid, endometrial, and other cancers. Patients with KLLN epimutations are at increased risk for breast and renal cancer compared to patients with PTEN mutations (Bennett et al., 2010).
  
Entity Breast cancer
Note Germline KLLN mutations have been identified in 3% of patients with apparently sporadic breast cancer (Nizialek et al., 2013). KLLN is thought to be a low-penetrance breast cancer susceptibility gene. KLLN mutations were not associated with breast cancer in a cohort of high-risk Australian and New Zealand patients (Thompson et al., 2012).
Somatic deletions of the KLLN gene are observed in 20% of breast tumors. Patients with somatic KLLN deletions are more likely to have estrogen receptor and progesterone receptor negative tumors and tumors of a basal sub-type (Nizialek et al., 2013).
Loss of KLLN expression is seen in all subtypes of breast cancer and decreased KLLN in breast tumors is associated with increased tumor grade and with breast cancer metastasis (Wang et al., 2013a).
  
Entity Renal cell carcinoma
Note 56% of patients with renal cell carcinoma were found to have germline KLLN promoter methylation of at least one of four CpG-rich regions housed in the genomic region between KLLN and PTEN. Somatic KLLN promoter methylation was also seen in renal tumors, possibly increasing with more advanced stage of disease (Bennett et al., 2011).
  
Entity Prostate cancer
Note KLLN mRNA expression is significantly decreased in prostate tumors compared to normal prostate tissue. Immunohistochemistry staining of prostate tumors for KLLN expression shows decreased staining associated with high Gleason score (Wang et al., 2013b).
  

External links

Nomenclature
HGNC (Hugo)KLLN   37212
Cards
AtlasKLLNID52121ch10q23
Entrez_Gene (NCBI)KLLN  100144748  killin, p53-regulated DNA replication inhibitor
GeneCards (Weizmann)KLLN
Ensembl (Hinxton)ENSG00000227268 [Gene_View]  chr10:89618918-89623194 [Contig_View]  KLLN [Vega]
ICGC DataPortalENSG00000227268
cBioPortalKLLN
AceView (NCBI)KLLN
Genatlas (Paris)KLLN
WikiGenes100144748
SOURCE (Princeton)NM_001126049
Genomic and cartography
GoldenPath (UCSC)KLLN  -  10q23.31   chr10:89618918-89623194 -  10q23   [Description]    (hg19-Feb_2009)
EnsemblKLLN - 10q23 [CytoView]
Mapping of homologs : NCBIKLLN [Mapview]
OMIM612105   615107   
Gene and transcription
Genbank (Entrez)EU552092
RefSeq transcript (Entrez)NM_001126049
RefSeq genomic (Entrez)AC_000142 NC_000010 NC_018921 NG_007466 NG_033079 NT_030059 NW_001838005 NW_004929376
Consensus coding sequences : CCDS (NCBI)KLLN
Cluster EST : UnigeneHs.559820 [ NCBI ]
CGAP (NCI)Hs.559820
Alternative Splicing : Fast-db (Paris)GSHG0004232
Alternative Splicing GalleryENSG00000227268
Gene ExpressionKLLN [ NCBI-GEO ]     KLLN [ SEEK ]   KLLN [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtB2CW77 (Uniprot)
NextProtB2CW77  [Medical]
With graphics : InterProB2CW77
Splice isoforms : SwissVarB2CW77 (Swissvar)
Related proteins : CluSTrB2CW77
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
DMDM Disease mutations100144748
Blocks (Seattle)B2CW77
Human Protein AtlasENSG00000227268 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasB2CW77
IPIIPI00890812   
Protein Interaction databases
DIP (DOE-UCLA)B2CW77
IntAct (EBI)B2CW77
FunCoupENSG00000227268
BioGRIDKLLN
InParanoidB2CW77
Interologous Interaction database B2CW77
IntegromeDBKLLN
STRING (EMBL)KLLN
Ontologies - Pathways
Ontology : AmiGODNA binding  nucleus  apoptotic process  cell cycle  
Ontology : EGO-EBIDNA binding  nucleus  apoptotic process  cell cycle  
Protein Interaction DatabaseKLLN
Wikipedia pathwaysKLLN
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)KLLN
snp3D : Map Gene to Disease100144748
SNP (GeneSNP Utah)KLLN
SNP : HGBaseKLLN
Genetic variants : HAPMAPKLLN
Exome VariantKLLN
1000_GenomesKLLN 
ICGC programENSG00000227268 
Somatic Mutations in Cancer : COSMICKLLN 
CONAN: Copy Number AnalysisKLLN 
Mutations and Diseases : HGMDKLLN
Mutations and Diseases : intOGenKLLN
Genomic VariantsKLLN  KLLN [DGVbeta]
dbVarKLLN
ClinVarKLLN
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM612105    615107   
MedgenKLLN
GENETestsKLLN
Disease Genetic AssociationKLLN
Huge Navigator KLLN [HugePedia]  KLLN [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneKLLN
Homology/Alignments : Family Browser (UCSC)KLLN
Phylogenetic Trees/Animal Genes : TreeFamKLLN
Chemical/Protein Interactions : CTD100144748
Clinical trialKLLN
Cancer Resource (Charite)ENSG00000227268
Other databases
Probes
Litterature
PubMed9 Pubmed reference(s) in Entrez
CoreMineKLLN
iHOPKLLN
OncoSearchKLLN

Bibliography

Killin is a p53-regulated nuclear inhibitor of DNA synthesis.
Cho YJ, Liang P.
Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5396-401. doi: 10.1073/pnas.0705410105. Epub 2008 Apr 2.
PMID 18385383
 
Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome.
Bennett KL, Mester J, Eng C.
JAMA. 2010 Dec 22;304(24):2724-31. doi: 10.1001/jama.2010.1877.
PMID 21177507
 
Germline and somatic DNA methylation and epigenetic regulation of KILLIN in renal cell carcinoma.
Bennett KL, Campbell R, Ganapathi S, Zhou M, Rini B, Ganapathi R, Neumann HP, Eng C.
Genes Chromosomes Cancer. 2011 Aug;50(8):654-61. doi: 10.1002/gcc.20887. Epub 2011 May 16.
PMID 21584899
 
Analysis of KLLN as a high-penetrance breast cancer predisposition gene.
Thompson ER, Gorringe KL, Choong DY, Eccles DM; kConFab, Mitchell G, Campbell IG.
Breast Cancer Res Treat. 2012 Jul;134(2):543-7. doi: 10.1007/s10549-012-2088-3. Epub 2012 May 13.
PMID 22580995
 
Germline and somatic KLLN alterations in breast cancer dysregulate G2 arrest.
Nizialek EA, Peterson C, Mester JL, Downes-Kelly E, Eng C.
Hum Mol Genet. 2013 Jun 15;22(12):2451-61. doi: 10.1093/hmg/ddt097. Epub 2013 Feb 27.
PMID 23446638
 
Androgen receptor-induced tumor suppressor, KLLN, inhibits breast cancer growth and transcriptionally activates p53/p73-mediated apoptosis in breast carcinomas.
Wang Y, He X, Yu Q, Eng C.
Hum Mol Genet. 2013a Jun 1;22(11):2263-72. doi: 10.1093/hmg/ddt077. Epub 2013 Feb 14.
PMID 23418309
 
Transcription factor KLLN inhibits tumor growth by AR suppression, induces apoptosis by TP53/TP73 stimulation in prostate carcinomas, and correlates with cellular differentiation.
Wang Y, Radhakrishnan D, He X, Peehl DM, Eng C.
J Clin Endocrinol Metab. 2013b Mar;98(3):E586-94. doi: 10.1210/jc.2012-3490. Epub 2013 Feb 5.
PMID 23386643
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written03-2013Emily Nizialek, Emma Lessieur, Charis Eng
Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA (EN, EL, CE); Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA (EN, EL, CE); Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA (CE); Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA (EN, CE); CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA (CE); HHMI Program in Molecular Medicine, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, 44195, USA (EL, CE)

Citation

This paper should be referenced as such :
Nizialek, E ; Lessieur, E ; Eng, C
KLLN (killin, p53-regulated DNA replication inhibitor)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(8):563-564.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/KLLNID52121ch10q23.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Tue Sep 23 18:52:13 CEST 2014

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