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PMID:19536131

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Citation

Lee, EW, Lee, MS, Camus, S, Ghim, J, Yang, MR, Oh, W, Ha, NC, Lane, DP and Song, J (2009) Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis. EMBO J. 28:2100-13

Abstract

Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. Interestingly, MKRN1 used earlier unknown sites, K291 and K292, for p53 ubiquitination and subsequent degradation. Under severe stress conditions, however, MKRN1 primarily induced the efficient degradation of p21. This regulatory process contributed to the acceleration of DNA damage-induced apoptosis by eliminating p21. MKRN1 depletion diminished adriamycin or ultraviolet-induced cell death, whereas ectopic expression of MKRN1 facilitated apoptosis. Furthermore, MKRN1 stable cell lines that constantly produced low levels of p53 and p21 exhibited stabilization of p53, but not p21, with increased cell death on DNA damage. Our results indicate that MKRN1 exhibits dual functions of keeping cells alive by suppressing p53 under normal conditions and stimulating cell death by repressing p21 under stress conditions.

Links

PubMed PMC2718286 Online version:10.1038/emboj.2009.164

Keywords

Animals; Apoptosis; Cell Cycle; DNA Damage; Gene Knockdown Techniques; Humans; Mice; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Proteasome Endopeptidase Complex; Ribonucleoproteins/genetics; Ribonucleoproteins/metabolism; Tumor Suppressor Protein p53/metabolism; Ubiquitination; rho GTP-Binding Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:P53

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P0CG48

F

Seeded From UniProt

complete

HUMAN:P53

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UHC7

F

Seeded From UniProt

complete

HUMAN:UBC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P04637

F

Seeded From UniProt

complete

HUMAN:CDN1A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UHC7

F

Seeded From UniProt

complete

HUMAN:MKRN1

involved_in

GO:0000209: protein polyubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MKRN1

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MKRN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P04637

F

Seeded From UniProt

complete

HUMAN:MKRN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P38936

F

Seeded From UniProt

complete

Notes

See also

References

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