HGNC Approved Gene Symbol: KLLN
Cytogenetic location: 10q23.31 Genomic coordinates (GRCh38): 10:87,859,158-87,863,533 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.31 | Cowden syndrome 4 | 615107 | 3 |
KLLN is a high-affinity DNA-binding protein that functions as a transcription factor (Wang et al., 2013).
Using differential display to identify p53 (TP53; 191170)-induced transcripts in human cancer cell lines, followed by screening a kidney cDNA library, Cho and Liang (2008) cloned KLLN. The deduced 178-amino acid protein has 2 nuclear localization signals and a calculated molecular mass of 30 kD. Northern blot analysis detected a 4.0-kb transcript expressed at low levels only in kidney and lung. Western blot analysis of fractionated cells showed killin in the nuclear compartment. Fluorescence-tagged killin localized to nuclei and had a 'beads on a string' appearance characteristic of DNA-binding proteins.
Cho and Liang (2008) found that expression of killin was induced by ectopic expression of p53 and by activation of endogenous p53 in response to genotoxic stress in human cell lines, and killin expression triggered S phase growth arrest followed by apoptosis. Chromatin immunoprecipitation analysis and reporter gene assays showed that p53 bound and activated the killin promoter. Knockdown of killin blocked p53-mediated apoptosis but had no effect on p53-induced p21 (CDKN1A; 116899) expression or growth arrest at G1 phase. In vitro-translated killin bound both single- and double-stranded DNA. Mutation analysis localized the DNA-binding and cytotoxic domain to 42 amino acids near the N terminus. This domain contains multiple WxxR or KxxW motifs and is rich in basic amino acids. A peptide covering this region bound double- and single-stranded DNA and an artificial replication fork, and it inhibited DNA synthesis in vitro and in vivo. Cho and Liang (2008) concluded that killin mediates p53-induced S phase checkpoint control and eliminates precancerous cells should they escape p21-mediated G1 blockade.
By analyzing 188 normal breast tissues and 1,247 malignant breast cancers of various subtypes, Wang et al. (2013) found that loss of KLLN was associated with tumor progression and increasing histologic grade in invasive carcinomas. In androgen receptor (AR; 313700)-positive breast cancer cell lines, but not AR-negative cell lines, dihydrotestosterone activated expression of both KLLN and PTEN from their shared bidirectional promoter. In turn, KLLN directly promoted expression of TP53 (191170) and TP73 (601990) with consequent elevated apoptosis and cell cycle arrest.
By genomic sequence analysis, Cho and Liang (2008) mapped the KLLN gene to chromosome 10q23 in close proximity to the PTEN gene (601728).
Cho and Liang (2008) determined that the KLLN gene contains 1 exon. The 194-bp region that separates the KLLN and PTEN genes contains a p53-binding promoter that appears responsive for both PTEN and KLLN.
Bennett et al. (2010) showed that there are 2 distinct p53 binding sites, one for KLLN and the other for PTEN. The PTEN p53 binding site was outside of the germline methylated region, whereas the putative KLLN p53 binding site was within the methylated region.
Bennett et al. (2010) found that germline KLLN promoter epigenetic modification (hypermethylation; 612105.0001) accounted for one-third of germline PTEN mutation-negative Cowden syndrome and of those whose phenotypic features resemble Cowden syndrome (see CWS4, 615107), prominently those with breast and thyroid disease. In their series, more than 40% of PTEN mutation-negative classic Cowden syndrome and 33% of mutation-negative Cowden-like syndrome patients had germline epigenetic inactivation of the KLLN promoter.
Among 123 patients with a clinical diagnosis of Cowden or Cowden-like syndrome (CWS4; 615107) without germline PTEN (601728), SDHB (185470) or SDHD (602690) mutations, Bennett et al. (2010) found that 45 (37%) had germline hypermethylation and epigenetic inactivation of the KLLN promoter. Of the 45 patients, 20 had classic Cowden syndrome, and 25 had Cowden-like syndrome. Hypermethylation of this region was not observed in 50 controls. Germline methylation was found to transcriptionally downregulate KLLN expression 250-fold and exclusively disrupted TP53 (191170) activation of KLLN by 30%. Analysis of clinical features showed that individuals with KLLN promoter methylation had a 3-fold increased prevalence of breast cancer and a greater than 2-fold increase of kidney cancer compared to individuals with germline PTEN mutations. Bennett et al. (2010) emphasized that the findings needed to be replicated.
Bennett, K. L., Mester, J., Eng, C. Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome. J.A.M.A. 304: 2724-2731, 2010. [PubMed: 21177507] [Full Text: https://doi.org/10.1001/jama.2010.1877]
Cho, Y., Liang, P. Killin is a p53-regulated nuclear inhibitor of DNA synthesis. Proc. Nat. Acad. Sci. 105: 5396-5401, 2008. [PubMed: 18385383] [Full Text: https://doi.org/10.1073/pnas.0705410105]
Wang, Y., He, X., Yu, Q., Eng, C. Androgen receptor-induced tumor suppressor, KLLN, inhibits breast cancer growth and transcriptionally activates p53/p73-mediated apoptosis in breast carcinomas. Hum. Molec. Genet. 22: 2263-2272, 2013. [PubMed: 23418309] [Full Text: https://doi.org/10.1093/hmg/ddt077]