Cell cycle specific distribution of killin: evidence for negative regulation of both DNA and RNA synthesis

Qiao, Man; Luo, Di; Kuang, Yi; Hong, Feng; Luo, Guangping; Peng, Liang

doi:10.1080/15384101.2015.1038686

Cited by 4 publications

(2 citation statements)

References 33 publications

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“…A technical limitation of our study is the lack of a trustworthy KLLN antibody. This observation has also been previously noted 40 . Therefore, we were unable to confirm the protein expression of KLLN in our studies.…”

Section: Discussionsupporting

confidence: 88%

KLLN-mediated DNA damage-induced apoptosis is associated with regulation of p53 phosphorylation and acetylation in breast cancer cells

Sankunny

Eng

2018

Cell Death Discov.

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KLLN is a target of p53 involved in S-phase cell cycle regulation deemed necessary and sufficient for p53-mediated apoptosis. Germline promoter hypermethylation of KLLN is associated with a cancer-predisposition syndrome, Cowden syndrome. KLLN’s DNA-binding ability is associated with transcription regulation and maintenance of genomic stability. Here, we report on KLLN’s role in DNA damage response (DDR) mediated through apoptosis in breast cells with and without a cancer phenotype. KLLN expression was upregulated after doxorubicin-induced DNA damage and this upregulation can be abrogated using RNAi-mediated gene silencing. Silencing KLLN after doxorubicin treatment effected DDR shown by decreased γ-H2AX foci and expression, and apoptosis assessed by decreased frequency of apoptotic nuclei and decreased expression of definitive markers of apoptosis. Contrary to expectations, there was no change in cell cycle regulation after KLLN silencing. These results were observed in breast cells with wildtype and mutant p53. At early timepoints after doxorubicin treatment, knocking down KLLN resulted in decreased Ser15-phosphorylation of p53 but not Thr68-phosphorylation of CHK2 or the phosphorylation of upstream regulators such as ATM and ATR. Interestingly, a second pathway for p53 activation was also affected by knockdown of KLLN. After doxorubicin treatment, Thr454-phosphorylation of DBC1, required to inhibit deacetylation of p53 by SIRT1, was decreased and therefore acetylation of p53 was also decreased with KLLN knockdown. Therefore, our observations suggest that KLLN’s role in DNA damage-induced apoptosis is likely independent of p53 and is associated with a two-pronged regulation of p53 activation.

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Section: Discussionsupporting

confidence: 88%

KLLN-mediated DNA damage-induced apoptosis is associated with regulation of p53 phosphorylation and acetylation in breast cancer cells

Sankunny

Eng

2018

Cell Death Discov.

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“…A technical limitation of our study is the inability to detect native KLLN protein due to the lack of reliable KLLN antibodies [ 14 , 26 ]. None of the commercially available KLLN antibodies have passed our intense quality control protocol.…”

Section: Discussionmentioning

confidence: 99%

Identification of nuclear export signal in KLLN suggests potential role in proteasomal degradation in cancer cells

Sankunny

Eng

2020

Oncotarget

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Germline and somatic promoter hypermethylation of KLLN has been found in diverse heritable and sporadic cancers, respectively. KLLN has many identified tumor suppressor functions, and when first reported, was thought to be exclusively nuclear. Here, we report on KLLN localization in both the nucleus and cytoplasm and the identification of a putative nuclear export signal (NES) sequence. KLLN overexpression in colon and breast cancer cells showed both nuclear and cytoplasmic presence. Inhibition of the CRM1 export pathway increased nuclear sequestration of KLLN, confirming the prediction of an NES sequence. Point mutations introduced in the predicted NES sequence decreased the strength of the NES and increased the nuclear sequestration of KLLN. Contrary to expectations, the transcription regulation and cellular proliferation functions of KLLN were unaffected by increased KLLN nuclear sequestration. Instead, increased nuclear KLLN correlated with increased nuclear sequestration of TRIM25 and decreased inhibitory phosphorylation of MDM2. Computational analysis of The Cancer Genome Atlas (TCGA) dataset showed positive correlation among KLLN, TRIM25 and MDM2 expression; pathway analysis of the common genes downstream of these three genes revealed protein degradation as one of the top canonical pathways. Together, our observations suggest that CRM1 pathway-based nuclear export of KLLN may impact proteasomal degradation.

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p53-mediated G1 arrest requires the induction of both p21 and Killin in human colon cancer cells

Luo

et al. 2021

Cell Cycle

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Cell cycle specific distribution of killin: evidence for negative regulation of both DNA and RNA synthesis

Abstract: These authors contributed equally to this work.

Cited by 4 publications

References 33 publications

KLLN-mediated DNA damage-induced apoptosis is associated with regulation of p53 phosphorylation and acetylation in breast cancer cells

KLLN-mediated DNA damage-induced apoptosis is associated with regulation of p53 phosphorylation and acetylation in breast cancer cells

Identification of nuclear export signal in KLLN suggests potential role in proteasomal degradation in cancer cells

p53-mediated G1 arrest requires the induction of both p21 and Killin in human colon cancer cells

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