KLLN (killin, p53-regulated DNA replication inhibitor)

2013-03-01   Emily Nizialek , Emma Lessieur , Charis Eng 

Identity

HGNC
LOCATION
10q23.31
LOCUSID
ALIAS
CWS4,KILLIN

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.

Proteins

Note

Calculated molecular weight: 19827 Da.
Atlas Image
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 name
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 name
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 name
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 name
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).

Bibliography

Pubmed IDLast YearTitleAuthors
215848992011Germline and somatic DNA methylation and epigenetic regulation of KILLIN in renal cell carcinoma.Bennett KL et al
183853832008Killin is a p53-regulated nuclear inhibitor of DNA synthesis.Cho YJ et al
234466382013Germline and somatic KLLN alterations in breast cancer dysregulate G2 arrest.Nizialek EA et al
225809952012Analysis of KLLN as a high-penetrance breast cancer predisposition gene.Thompson ER et al
234183092013Androgen receptor-induced tumor suppressor, KLLN, inhibits breast cancer growth and transcriptionally activates p53/p73-mediated apoptosis in breast carcinomas.Wang Y et al
233866432013Transcription factor KLLN inhibits tumor growth by AR suppression, induces apoptosis by TP53/TP73 stimulation in prostate carcinomas, and correlates with cellular differentiation.Wang Y et al

Other Information

Locus ID:

NCBI: 100144748
MIM: 612105
HGNC: 37212
Ensembl: ENSG00000227268

Variants:

dbSNP: 100144748
ClinVar: 100144748
TCGA: ENSG00000227268
COSMIC: KLLN

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000227268ENST00000445946B2CW77

Expression (GTEx)

0
1
2
3
4
5

References

Pubmed IDYearTitleCitations
211775072010Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome.49
219564142011Incidence and clinical characteristics of thyroid cancer in prospective series of individuals with Cowden and Cowden-like syndrome characterized by germline PTEN, SDH, or KLLN alterations.39
183853832008Killin is a p53-regulated nuclear inhibitor of DNA synthesis.23
183853832008Killin is a p53-regulated nuclear inhibitor of DNA synthesis.23
233866432013Transcription factor KLLN inhibits tumor growth by AR suppression, induces apoptosis by TP53/TP73 stimulation in prostate carcinomas, and correlates with cellular differentiation.13
243568152014Activation of AR sensitizes breast carcinomas to NVP-BEZ235's therapeutic effect mediated by PTEN and KLLN upregulation.9
287551402017Circulating levels of PTEN and KLLN in papillary thyroid carcinoma: can they be considered as novel diagnostic biomarkers?6
256694292015KLLN epigenotype-phenotype associations in Cowden syndrome.2
215848992011Germline and somatic DNA methylation and epigenetic regulation of KILLIN in renal cell carcinoma.0
225809952012Analysis of KLLN as a high-penetrance breast cancer predisposition gene.0

Citation

Emily Nizialek ; Emma Lessieur ; Charis Eng

KLLN (killin, p53-regulated DNA replication inhibitor)

Atlas Genet Cytogenet Oncol Haematol. 2013-03-01

Online version: http://atlasgeneticsoncology.org/gene/52121/klln