Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis

Lee, Eun Woo; Lee, Min Sik; Camus, Suzanne; Ghim, Jaewang; Yang, Mina; Oh, Wonkyung; Ha, Nam Chul; Lane, David P.; Song, Jaewhan

doi:10.1038/emboj.2009.164

Cited by 135 publications

(151 citation statements)

References 69 publications

(121 reference statements)

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“…The ubiquitylation assay was performed as described previously. 56 Briefly, cells were lysed in 6 M guanidine-HCl buffer (pH 8) containing 5 mM NEM (Sigma-Aldrich), and His-ubiquitin-conjugated proteins were purified by Ni 2+ -NTA (Qiagen, Valencia, CA, USA) and analyzed by western blotting (WB). For ubiquitylation assays using HA-Ub, cells were lysed under denaturing conditions containing 1% SDS.…”

Section: Discussionmentioning

confidence: 99%

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

Seong

Seo

et al. 2015

Cell Death Differ

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Given their crucial role in apoptosis suppression, inhibitor of apoptosis proteins (IAPs) have recently become attractive targets for cancer therapy. Here, we report that cellular IAP2 (cIAP2) is specifically stabilized in several cancer cell lines, leading to resistance to Smac mimetics, such as BV6 and birinapant. In particular, our results showed that cIAP2 depletion, but not cIAP1 depletion, sensitized cancer cells to Smac mimetic-induced apoptosis. Ubiquitin-specific protease 11 (USP11) is a deubiquitylase that directly stabilizes cIAP2. USP11 overexpression is frequently found in colorectal cancer and melanoma and is correlated with poor survival. In our study, cancer cell lines expressing high levels of USP11 exhibited strong resistance to Smac mimetic-induced cIAP2 degradation. Furthermore, USP11 downregulation sensitized these cells to apoptosis induced by TRAIL and BV6 and suppressed tumor growth in a xenograft model. Finally, the TNFα/JNK pathway induced USP11 expression and maintained cIAP2 stability, suggesting an alternative TNFα-dependent cell survival pathway. Collectively, our data suggest that USP11-stabilized cIAP2 may serve as a barrier against IAP-targeted clinical approaches.

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Section: Discussionmentioning

confidence: 99%

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

Seong

Seo

et al. 2015

Cell Death Differ

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“…MKRN1, a protein highly conserved from invertebrates to vertebrates, has a ubiquitous expression pattern in various tissues 25 and functions as an E3 ubiquitin ligase for various substrates 24,26,27 . Previous reports showed that MKRN1 was able to suppress p53 function, and regulate cell growth and apoptosis.…”

Section: Depletion Of Mkrn1 Induces Dr-mediated Extrinsic Apoptosismentioning

confidence: 99%

“…As MKRN1 is an E3 ubiquitin ligase 24,26,27 , we next asked whether MKRN1 E3 ligase activity affected the stability of proteins involved in DISC complexes. When MKRN1 was knocked-down by siRNA or short-hairpin RNA (shRNA), MKRN1 protein was barely detected and MKRN1 messenger RNA levels were reduced up to 70-80% of control mRNAs (Fig.…”

Section: Fadd Ubiquitination and Degradation Is Mkrn1-dependentmentioning

confidence: 99%

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Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis

et al. 2012

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Fas-associated protein with death domain (FADD) is a pivotal component of death receptormediated extrinsic apoptosis and necroptosis. Here we show that FADD is regulated by makorin Ring Finger Protein 1 (mKRn1) E3 ligase-mediated ubiquitination and proteasomal degradation. mKRn1 knockdown results in FADD protein stabilization and formation of the rapid deathinducing signalling complex, which causes hypersensitivity to extrinsic apoptosis by facilitating caspase-8 and caspase-3 cleavage in response to death signals. We also show that mKRn1 and FADD are involved in the regulation of necrosome formation and necroptosis upon caspase inhibition. Downregulation of mKRn1 results in severe defects of tumour growth upon tumour necrosis factor-related apoptosis-inducing ligand treatment in a xenograft model using mDAmB-231 breast cancer cells. suppression of tumour growth by mKRn1 depletion is relieved by simultaneous FADD knockdown. our data reveal a novel mechanism by which fas-associated protein with death domain is regulated via an ubiquitination-induced degradation pathway. A poptosis, or programmed cell death, can be initiated by intrinsic or extrinsic pathways 1,2 . Intrinsic pathways are triggered by mitochondrial permeabilization, which results in the release of cytochrome c and the formation of an apoptosome complex, leading to caspase-9 activation 3 . Extrinsic pathways can be induced by activation of death receptors (DRs), such as TNFR1, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and Fas/CD95 by their corresponding ligands; receptor activation triggers the formation of the death-inducing signalling complex (DISC) or TNFR complex II, which comprises caspase-8 and fas-associated protein with death domain (FADD). These complexes ultimately activate caspase-8, thereby causing extrinsic apoptosis 3,4 . In addition to inducing extrinsic apoptosis, caspase-8 and FADD are known to suppress necroptosis under various conditions [5][6][7][8][9][10][11] .DR downstream pathways are regulated in various ways. For example, cFLIP (cellular FLICE inhibitory protein) competes with caspase-8 for binding to FADD, preventing DISC formation 12 . The levels and activities of cFLIP are controlled by numerous factors including NF-κB, Akt, JNK, Srk and ITCH [13][14][15][16][17] . CARP-1 and -2, which are E3 ubiquitin ligases for caspase-8, are also known to suppress TRAIL activation 18 . Post-translational modifications such as O-glycosylation, S-nitrosylation and S-palmitoylation of DRs have also been identified to regulate death signalling 19 . However, phosphorylation of FADD, the only post-translational modification that FADD is known to undergo, is not involved in the induction of apoptosis. Rather, this modification seems to be essential for the pro-survival roles of nuclear-localized phospho-FADD [20][21][22][23] . Other post-translational modifications affecting the apoptotic and necroptotic activities of FADD have yet to be identified.Here, we show that Makorin Ring Finger Protein 1 (MKRN1), an...

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“…Apparently, MKRN1 exhibits divergent functions both in the cell nucleus and the cytoplasm. As an E3 ubiquitin ligase it acts on itself and the catalytic subunit of human telomerase reverse transcriptase (26), p53 and p21 (27). Furthermore, MKRN1 modulates RNA polymerase II-mediated transcription (28) and may play a role in mRNA decay (29).…”

mentioning

confidence: 99%

Makorin Ring Zinc Finger Protein 1 (MKRN1), a Novel Poly(A)-binding Protein-interacting Protein, Stimulates Translation in Nerve Cells

Miroci

Schob

Kindler

et al. 2012

Journal of Biological Chemistry

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Background: Synaptic activity induces translation of mRNAs in dendrites of neurons. Results: Makorin 1 (MKRN1) interacts with poly(A)-binding protein, stimulates translation, accumulates in neuronal dendrites after plasticity-inducing stimuli, and is associated with dendritic mRNAs. Conclusion: MKRN1 has the potential to locally control the translation of dendritic mRNAs at synapses. Significance: MKRN1 is a novel positive regulator of translation.

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Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis

Cited by 135 publications

References 69 publications

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis

Makorin Ring Zinc Finger Protein 1 (MKRN1), a Novel Poly(A)-binding Protein-interacting Protein, Stimulates Translation in Nerve Cells

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