Affinage

MCL1

Induced myeloid leukemia cell differentiation protein Mcl-1 · UniProt Q07820

Length
350 aa
Mass
37.3 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MCL-1 is an anti-apoptotic BCL-2 family protein that maintains pro-apoptotic effectors in an inactive state at the mitochondrion to prevent commitment to programmed cell death (PMID:14633975). Its core survival function rests on its BH3-binding groove, which holds BAK in an inactive complex; loss of MCL-1 releases BAK and licenses apoptosis (PMID:14633975), and an allosteric cysteine (C286) distant from this groove tunes BH3 binding and BAX suppression (PMID:27159560). The anti-apoptotic activity is restricted to the outer mitochondrial membrane, whereas a separable matrix-localized pool supports mitochondrial respiration and morphology — cardiac ablation of Mcl-1 causes fatal cardiomyopathy with respiratory defects that persist even when apoptosis is blocked by Bax/Bak co-deletion (PMID:23788622, PMID:23026029). Beyond apoptosis, MCL-1 acts as a transcriptional master regulator of fatty acid oxidation independently of its apoptotic role (PMID:36198266), is recruited to DNA double-strand breaks to support ATR-Chk1 checkpoint signaling and genome integrity (PMID:20647761), and functions as a switch between homologous recombination and non-homologous end-joining by directly binding the Ku complex through its BH1/BH3 domains (PMID:29227281). MCL-1 also directly binds and activates Akt via its PEST domain (PMID:31662324) and modulates mitophagy through LC3-interacting regions and interaction with the receptor Bnip3 (PMID:35563775). The protein is short-lived and its abundance is set by a dense post-translational network: GSK3β-, PKCθ- and ERK-dependent phosphorylation (notably at Ser159/Thr163) primes it for ubiquitination by E3 ligases including SCF-Fbw7 and FBXO4, opposed by PP2A-mediated dephosphorylation, stabilizing deubiquitinases (USP13, USP9x), and competing factors such as Skp2 and TRAF4 (PMID:21608150, PMID:28619760, PMID:19734538, PMID:33627786, PMID:35301297, PMID:36535926, PMID:33658484, PMID:28776569, PMID:36346691). MCL-1 can additionally be degraded ubiquitin-independently by the 20S proteasome (PMID:20385764), and its pro-survival versus pro-death balance is set upstream by alternative splicing that produces MCL-1L and MCL-1S isoforms (PMID:23284704, PMID:30468106, PMID:26538029).

Mechanistic history

Synthesis pass · year-by-year structured walk · 31 steps
  1. 2003 High

    Established the core anti-apoptotic mechanism: that MCL-1 directly restrains a pro-apoptotic effector rather than acting only as a general survival signal.

    Evidence Co-IP of MCL-1 with BAK plus rescue experiments in adenovirus-infected cells where E1A-driven MCL-1 loss releases BAK and triggers apoptosis

    PMID:14633975

    Open questions at the time
    • Did not resolve the structural basis of the BAK interaction
    • Did not address other effectors (BAX, BIM) in the same system
  2. 2003 Medium

    Showed MCL-1 abundance is controlled at multiple layers during apoptosis, distinguishing transcriptional, translational and proteasomal routes of loss.

    Evidence Promoter and IRES reporter assays, caspase and proteasome inhibitors, and eIF2α phosphorylation analysis

    PMID:12941295

    Open questions at the time
    • Did not identify the responsible E3 ligase
    • Mechanism linking caspase activity to mRNA loss not defined
  3. 2009 High

    Mapped a specific kinase-to-degradation axis by identifying Ser159 phosphorylation as a degradation trigger under lipotoxic stress.

    Evidence PKCθ genetic deletion, rottlerin inhibition, phospho-Ser159 immunoblot, and S159A mutant in primary hepatocytes

    PMID:19734538

    Open questions at the time
    • Did not identify the E3 ligase acting downstream of Ser159 phosphorylation
    • Generalizability beyond hepatocyte lipoapoptosis untested
  4. 2010 High

    Demonstrated MCL-1 degradation can be entirely ubiquitin-independent, revealing a 20S-proteasome route alongside the canonical ubiquitin pathway.

    Evidence Lysine-less MCL-1(KR) mutant, E1 inhibition, and cell-free 20S proteasome degradation of in vitro-translated MCL-1

    PMID:20385764

    Open questions at the time
    • Relative contribution of ubiquitin-dependent vs independent routes in vivo unclear
    • What targets MCL-1 to the 20S proteasome unresolved
  5. 2010 Medium

    Extended MCL-1 function into the DNA damage response, showing a nuclear/DSB role in checkpoint signaling distinct from mitochondrial apoptosis.

    Evidence Co-IP with γ-H2AX and NBS1, site-specific DSB recruitment, and delayed Chk1 phosphorylation in Mcl-1−/− MEFs

    PMID:20647761

    Open questions at the time
    • Direct molecular partner at the break site not defined here
    • How nuclear recruitment is regulated unknown
  6. 2012 Medium

    Resolved that MCL-1's apoptotic and metabolic functions are spatially separated within the mitochondrion.

    Evidence Subcellular fractionation and localization-variant functional studies (review synthesizing direct experiments)

    PMID:23026029

    Open questions at the time
    • Import mechanism into the matrix not defined
    • Molecular partners of the matrix pool unidentified
  7. 2013 High

    Provided in vivo proof that MCL-1 has an essential apoptosis-independent role in mitochondrial physiology.

    Evidence Cardiac-specific Mcl-1 KO with Bax/Bak epistasis, electron microscopy, and respiration assays

    PMID:23788622

    Open questions at the time
    • Molecular mechanism connecting MCL-1 to respiration not identified
    • Matrix interacting partners unknown
  8. 2007 Medium

    Linked MCL-1 turnover to anoikis and metastasis through a GSK-3β/proteasome/Bim axis.

    Evidence GSK-3β and proteasome inhibition, MCL-1/Bim knockdown, and metastatic vs non-metastatic cell comparison with in vivo metastasis assay

    PMID:18006817

    Open questions at the time
    • E3 ligase downstream of GSK-3β not identified here
    • Direct link to phospho-sites not mapped
  9. 2012 Medium

    Identified caveolin-1 as a stabilizing binding partner that protects MCL-1 from ubiquitination during anoikis.

    Evidence Co-IP, reciprocal Cav-1 overexpression/knockdown, and ubiquitination assays

    PMID:22277751

    Open questions at the time
    • Binding interface not mapped
    • Whether Cav-1 blocks a specific E3 unknown
  10. 2012 Medium

    Identified tankyrase 1 as an N-terminal binding partner regulating MCL-1 levels independent of ADP-ribosylation.

    Evidence Yeast two-hybrid, Co-IP, truncation mapping, and overexpression functional assays

    PMID:12475993

    Open questions at the time
    • Mechanism of level reduction not defined
    • Physiological relevance untested
  11. 2012 Medium

    Established splicing factor control of the MCL-1L/MCL-1S balance, defining an upstream determinant of pro- vs anti-apoptotic output.

    Evidence SRSF1/SRSF5 siRNA knockdown with RT-PCR splicing readout in breast cancer cells

    PMID:23284704

    Open questions at the time
    • Direct binding sites not mapped in this study
    • Context-dependence mechanism unclear
  12. 2018 Medium

    Expanded the splicing regulatory network and mapped binding sites controlling the pro-apoptotic MCL-1S switch.

    Evidence hnRNP F/H1/K knockdown, RNA-IP, MCL-1 minigene, and apoptosis assays

    PMID:30468106

    Open questions at the time
    • Interplay with SR proteins not resolved
    • In vivo relevance untested
  13. 2013 Medium

    Defined transcriptional control of MCL-1 by Notch1 through a direct promoter element in an immune context.

    Evidence ChIP at the MCL-1 promoter, gamma-secretase inhibition, and Notch1 siRNA in macrophages

    PMID:23872918

    Open questions at the time
    • Cofactors at the CSL site not defined
    • Generalizability beyond macrophages unknown
  14. 2014 Medium

    Linked Fbw7 loss to MCL-1 overexpression and BH3-mimetic resistance, establishing a clinically relevant degradation pathway.

    Evidence Ubiquitination assays, GSK3 inhibition, Fbw7 reconstitution and Mcl-1 knockdown in T-ALL lines

    PMID:21608150

    Open questions at the time
    • Phospho-degron not directly mapped here
    • Dependence on specific phospho-sites not defined
  15. 2014 Low

    Proposed STAT3 as a context-dependent partner that inverts MCL-1 function toward pro-apoptotic outcomes during implantation.

    Evidence MALDI-TOF, far-western, co-localization and co-transfection with apoptosis/invasion assays

    PMID:24481815

    Open questions at the time
    • No reciprocal Co-IP to confirm direct binding
    • Mechanism of functional inversion not defined
    • Single-lab limited follow-up
  16. 2016 High

    Identified an allosteric regulatory cysteine (C286) outside the BH3 groove that controls MCL-1's effector-suppressing capacity.

    Evidence Covalent C286 modification, C286W mutagenesis, in vitro BH3 binding and BAX suppression assays, and HDX-MS

    PMID:27159560

    Open questions at the time
    • Endogenous physiological ligand of C286 unknown
    • Whether oxidation modifies C286 in cells untested
  17. 2016 Medium

    Defined a mitosis-specific, ligase-independent route of MCL-1 degradation that gates taxol-induced mitotic apoptosis.

    Evidence siRNA of APC/C-Cdc20, FBW7, MULE, proteasome inhibition, time-lapse microscopy and MCL-1 gain/loss-of-function

    PMID:26769847

    Open questions at the time
    • The degradation machinery used during mitosis not identified
    • Mechanism of competition with Cyclin B1 unclear
  18. 2011 Medium

    Characterized a distinct 'reverse BH3' binding mode selective for the MCL-1 groove, informing inhibitor design.

    Evidence Phage display, NMR, fluorescence polarization displacement and alanine scanning

    PMID:21953453

    Open questions at the time
    • No endogenous rBH3 protein partner identified
    • Cellular relevance untested
  19. 2017 High

    Coupled Hsp90 inhibition to MCL-1 degradation via GSK3β-dependent phosphorylation and FBW7 recruitment, validated in vivo.

    Evidence GSK3β inhibition, phospho-mutant knock-in, ubiquitination assays and xenografts

    PMID:28619760

    Open questions at the time
    • Exact phospho-degron residues not fully delineated
    • Breadth across tumor types untested
  20. 2017 Medium

    Identified FBXO4 as an additional E3 ligase for MCL-1 influencing chemoresistance.

    Evidence Co-IP, ubiquitination assays, and reciprocal FBXO4 knockdown/overexpression

    PMID:28776569

    Open questions at the time
    • Phospho-dependence of FBXO4 recognition not defined
    • Relationship to Fbw7 not resolved
  21. 2017 High

    Revealed a nuclear function of MCL-1 as an HR/NHEJ switch via direct binding to Ku, decoupling DNA repair control from apoptosis.

    Evidence CRISPR/shRNA depletion, HR/NHEJ reporters, Co-IP with Ku, BH1/BH3 domain mutants, cell-cycle analysis and xenografts with MI-223

    PMID:29227281

    Open questions at the time
    • How MCL-1 is recruited to chromatin not fully defined
    • Structural basis of Ku inhibition unresolved
  22. 2018 Medium

    Showed that Bim phosphorylation feeds back to control MCL-1 stability and binding specificity, enforcing MCL-1 dependence.

    Evidence Phospho-mimetic/deficient Bim mutants, Co-IP, and MCL-1 stability and viability assays

    PMID:29775995

    Open questions at the time
    • Kinase responsible for Bim phosphorylation not defined here
    • Generalizability beyond the WM model untested
  23. 2019 High

    Established a direct MCL-1–Akt interaction in which the PEST domain activates Akt, defining a pro-tumorigenic signaling role.

    Evidence CRISPR/shRNA depletion, Co-IP, PEST/PH domain mapping, Akt activity assays, xenografts and the disruptor PH-687

    PMID:31662324

    Open questions at the time
    • Structural model of the PEST/PH interface not solved
    • Relationship to mitochondrial MCL-1 pool unclear
  24. 2020 Medium

    Showed the MCL-1 transmembrane domain self- and hetero-oligomerizes and that cancer mutations in it enhance anti-apoptotic activity.

    Evidence Oligomerization and fractionation assays, Bok TMD heterooligomerization, ER-mitochondria contact analysis, and TMD-variant mutagenesis

    PMID:33093207

    Open questions at the time
    • Physiological role of TMD oligomers in normal cells unclear
    • Structural arrangement of oligomers undefined
  25. 2021 Medium

    Identified USP13 as a deubiquitinase that stabilizes MCL-1, adding a stabilizing arm to the turnover network.

    Evidence Co-IP, ubiquitination assays, siRNA, proliferation assays and tissue IHC correlation in cervical cancer

    PMID:33627786

    Open questions at the time
    • Binding interface not mapped
    • Whether USP13 competes with specific E3s untested
  26. 2021 Medium

    Established PP2A as the phosphatase that opposes degradative phosphorylation at Ser159/Thr163, completing a kinase-phosphatase switch.

    Evidence Phosphatase siRNA screen, okadaic acid inhibition, phospho-specific blotting and half-life measurements in myeloma

    PMID:33658484

    Open questions at the time
    • Direct PP2A–MCL-1 contact not demonstrated
    • Targeting subunit of PP2A unknown
  27. 2022 High

    Defined MCL-1 as a transcriptional master regulator of fatty acid oxidation independent of apoptosis, a genuinely separable function.

    Evidence Mcl-1 genetic deletion with metabolomic/proteomic/genomic profiling and glucose-withdrawal lethality in apoptosis-deficient leukemia cells

    PMID:36198266

    Open questions at the time
    • How MCL-1 controls FAO gene transcription mechanistically unknown
    • Whether this requires a specific subcellular pool unresolved
  28. 2022 Medium

    Connected MCL-1 to selective mitophagy through Bnip3 binding and LIR motifs, distinguishing it from suppression of bulk autophagy.

    Evidence Cardiac MCL-1 overexpression, autophagic flux and mitophagy assays, Co-IP with Bnip3, and LIR mutagenesis

    PMID:35563775

    Open questions at the time
    • LIR-mediated LC3 binding not directly biophysically confirmed
    • Crosstalk with apoptotic function unresolved
  29. 2022 Medium

    Identified Skp2 as a stabilizing factor that competes with FBW7 to control MCL-1-dependent radioresistance.

    Evidence Co-IP, ubiquitination analysis, Skp2 CRISPR knockout, and xenografts in colorectal cancer

    PMID:35301297

    Open questions at the time
    • Mechanism of competition with FBW7 not structurally defined
    • Whether Skp2 acts catalytically or by occlusion unclear
  30. 2022 Medium

    Connected TRAF4 to MCL-1 stability through a TRAF4-Akt-GSK3β axis converging on Ser159 and the deubiquitinase JOSD1.

    Evidence Co-IP of TRAF4 with Akt and MCL-1, GSK3β activity assays, phospho-S159 blotting, TRAF4 KO and xenografts

    PMID:36535926

    Open questions at the time
    • Direct JOSD1–MCL-1 interaction interface not mapped
    • Hierarchy among the many stabilizing factors unresolved
  31. 2023 Medium

    Showed that BH3-mimetic MCL-1 inhibitors paradoxically stabilize MCL-1 protein by enhancing USP9x deubiquitination and dissociating partners.

    Evidence Half-life assays, RPPA, Co-IP, in vitro ubiquitination/deubiquitination, DUB inhibitor (WP1130) and modeling

    PMID:36346691

    Open questions at the time
    • Mechanism by which inhibitor binding triggers USP9x recruitment unclear
    • Clinical implications of induced stabilization untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MCL-1's spatially and functionally distinct activities — outer-membrane apoptosis suppression, matrix respiration, nuclear DNA-repair switching, Akt activation and FAO transcription — are coordinated and selectively regulated by its turnover network remains unresolved.
  • No unifying model links the subcellular pools to specific degradation routes
  • Structural basis for non-apoptotic interactions (Ku, Akt, Bnip3) undefined
  • Mechanism of transcriptional FAO control unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140313 molecular sequestering activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005739 mitochondrion 2
Pathway
R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2 R-HSA-1430728 Metabolism 1 R-HSA-9612973 Autophagy 1
Partners
AKTBAKBAXBIMBNIP3FBW7KUUSP13

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 In uninfected cells, BAK is complexed with MCL-1. Upon adenovirus E1A expression, MCL-1 is specifically down-regulated through protein destabilization and mRNA loss, releasing BAK from the MCL-1-BAK complex. Loss of MCL-1 was required to initiate apoptosis, as restoration of MCL-1 expression rescued infected cells from E1A-induced apoptosis. MCL-1 thus maintains BAK in an inactive state. Co-immunoprecipitation, Western blotting, rescue expression experiments in adenovirus-infected cells Genes & development High 14633975
2002 Tankyrase 1 physically interacts with both MCL-1L and MCL-1S isoforms via its first 10 ankyrin repeats binding to a 25-amino-acid stretch in the N-terminus of MCL-1. Overexpression of tankyrase 1 antagonizes MCL-1L-mediated cell survival and MCL-1S-induced cell death, and decreases MCL-1 protein levels. No ADP-ribosylation of MCL-1 was detected; instead, MCL-1 overexpression suppresses ADP-ribosylation of the tankyrase substrate TRF1. Yeast two-hybrid screening, co-immunoprecipitation in mammalian cells, truncation mutant analysis, overexpression functional assays The Journal of biological chemistry Medium 12475993
2010 MCL-1 degradation can occur independently of ubiquitination. An MCL-1 mutant lacking all lysine residues (MCL-1(KR)) that cannot be ubiquitinated is degraded at a rate similar to wild-type MCL-1 under both basal and stressed conditions. Unmodified, in vitro-translated MCL-1 is degraded by the 20S proteasome in a cell-free system. Ubiquitination-deficient MCL-1(KR) mutant expression, blocking E1 ubiquitin-activating enzyme, in vitro 20S proteasome degradation assay, primary lymphocyte experiments Molecular and cellular biology High 20385764
2010 MCL-1 localizes to sites of DNA double-strand breaks (co-localizes with γ-H2AX and NBS1 by immunoprecipitation and immunofluorescence, and is directly recruited adjacent to DSB sites). MCL-1-deficient MEFs show delayed Chk1 phosphorylation and delayed γ-H2AX appearance after etoposide treatment. Loss of MCL-1 results in greater accumulation of chromosomal abnormalities after repeated etoposide treatment, indicating a role in DNA damage checkpoint response and genome integrity. Co-immunoprecipitation with γ-H2AX and NBS1, immunofluorescence co-staining, site-specific DSB recruitment assay, comparison of Mcl-1−/− vs. wild-type MEFs, chromosomal aberration analysis Cell cycle (Georgetown, Tex.) Medium 20647761
2013 Cardiac-specific ablation of Mcl-1 results in fatal dilated cardiomyopathy with loss of cardiac contractility, abnormal mitochondrial ultrastructure, and defective mitochondrial respiration. Genetic co-deletion of Bax and Bak largely rescues lethality and cardiac function, but mitochondrial ultrastructural abnormalities and deficient respiration persist, indicating that MCL-1 has a function in mitochondrial physiology beyond apoptosis suppression. Conditional cardiac-specific Mcl-1 knockout mice, genetic epistasis with Bax/Bak double knockout, electron microscopy of mitochondrial ultrastructure, mitochondrial respiration assays Genes & development High 23788622
2012 MCL-1's antiapoptotic activity is restricted to the outer mitochondrial membrane (OMM), whereas its function in maintaining normal mitochondrial morphology and energy production requires localization to the matrix. These two functions depend on separate mitochondrial sublocalizations. Subcellular fractionation, functional studies with localization variants (review synthesizing multiple experimental studies) Trends in cell biology Medium 23026029
2014 SCF-Fbw7 E3 ubiquitin ligase mediates MCL-1 ubiquitination and proteasomal degradation in a GSK3 phosphorylation-dependent manner. Loss of Fbw7 tumor suppressor results in MCL-1 overexpression and resistance to ABT-737. Reconstitution of Fbw7 or depletion of MCL-1 in Fbw7-deficient cells restores ABT-737 sensitivity. Ubiquitination assays, GSK3 inhibition experiments, Fbw7 reconstitution, Mcl-1 siRNA knockdown, cell viability assays in T-ALL cell lines Oncotarget Medium 21608150
2017 Hsp90 inhibition promotes GSK3β-dependent phosphorylation of MCL-1, which then binds to FBW7 and undergoes ubiquitination and proteasomal degradation. Blocking MCL-1 phosphorylation by genetic knock-in abrogates its degradation and confers resistance to Hsp90 inhibitors in vitro and in vivo. GSK3β inhibitor experiments, Mcl-1 phospho-mutant knock-in, ubiquitination assays, FBW7 mutation analysis in colorectal cancer cells, in vivo xenograft models Molecular cancer therapeutics High 28619760
2009 MCL-1 is rapidly degraded in hepatocytes in response to palmitate via a PKCθ-dependent, proteasome-dependent pathway. PKCθ promotes phosphorylation of MCL-1 at Ser159. An MCL-1 S159A mutant is resistant to palmitate-induced degradation and improves cell survival. Overexpression of a ubiquitin-resistant MCL-1 mutant attenuates palmitate-induced lipoapoptosis. Proteasome inhibitor experiments, novel PKC inhibitor (rottlerin), shRNA knockdown of PKCθ, PKCθ genetic deletion in primary hepatocytes, phospho-immunoblot of MCL-1 Ser159, MCL-1 S159A mutant expression, ubiquitin-resistant Mcl-1 mutant overexpression The Journal of biological chemistry High 19734538
2007 Cell detachment from ECM rapidly degrades MCL-1 via a GSK-3β-dependent proteasomal pathway and transcriptionally up-regulates Bim. MCL-1 degradation in the presence of Bim is sufficient to induce anoikis. Dysregulation of this MCL-1 degradation/Bim induction axis contributes to anoikis resistance in metastatic cancer cells. GSK-3β inhibition, proteasome inhibitor experiments, knockdown of MCL-1 and Bim, comparison of non-metastatic vs. metastatic cell lines, in vivo metastasis assay Cancer research Medium 18006817
2017 MCL-1 acts as a functional switch between homologous recombination (HR) and non-homologous end-joining (NHEJ) DNA repair pathways. MCL-1 depletion reduces HR and enhances NHEJ, while MCL-1 overexpression increases HR over NHEJ. MCL-1 directly interacts with the Ku protein complex via its BH1 and BH3 domains to inhibit Ku-mediated NHEJ. MCL-1 also promotes DNA resection by the Mre11 complex. MCL-1 expression peaks in S/G2 phase in a cell-cycle-regulated manner during HR. CRISPR/Cas9 and shRNA depletion, HR/NHEJ reporter assays, co-immunoprecipitation of MCL-1 with Ku complex, domain deletion mutants (BH1, BH3), cell cycle analysis, in vivo lung cancer xenograft experiments with small molecule MI-223 The Journal of clinical investigation High 29227281
2019 MCL-1 directly interacts with Akt via its PEST domain binding to the pleckstrin homology (PH) domain of Akt. This Mcl-1/PH domain interaction disrupts intramolecular PH/kinase domain interactions of Akt, thereby activating Akt. Depletion of MCL-1 by CRISPR/Cas9 or shRNA significantly decreases Akt activity and suppresses lung cancer cell growth in vitro and in xenografts. CRISPR/Cas9 and shRNA depletion of MCL-1, co-immunoprecipitation of MCL-1 with Akt, domain-specific interaction mapping (PEST domain vs. PH domain), Akt activity measurements, xenograft models, small molecule PH-687 disruption of MCL-1/Akt interaction Cancer research High 31662324
2016 A cysteine residue (C286) at a site distant from the BH3-binding groove of MCL-1 serves as an allosteric regulatory site. Covalent small-molecule modification of C286 impairs the BH3 binding capacity of MCL-1 and its suppression of BAX, as recapitulated by C286W mutagenic mimicry in vitro and in mouse cells. Covalent small-molecule modification, C286W mutagenesis, structure-function analysis, in vitro BH3 binding assay, BAX suppression assay in mouse cells, hydrogen-deuterium exchange mass spectrometry Nature structural & molecular biology High 27159560
2012 SRSF1 and SRSF5 RNA-binding proteins regulate alternative splicing of MCL-1 pre-mRNA. Knockdown of SRSF1 shifts splicing toward pro-apoptotic MCL-1S in breast cancer cells. SRSF1 also affects MCL-1 protein stability and translation in a cell-context-dependent manner. siRNA knockdown of SRSF1 and SRSF5, RT-PCR splicing analysis, Western blotting in breast cancer and choriocarcinoma cell lines PloS one Medium 23284704
2018 hnRNP F, H1, and K RNA-binding proteins regulate alternative splicing of MCL-1 pre-mRNA. siRNA knockdown of hnRNP K and the hnRNP F/H family switches splicing toward pro-apoptotic MCL-1S. Specific binding sites for these factors were identified by RNA immunoprecipitation using a MCL-1 minigene construct. Triple knockdown achieves up to 30-fold increase in MCL-1S levels and activates the mitochondrial cell death pathway. siRNA knockdown, RT-PCR splicing analysis, RNA immunoprecipitation, MCL-1 minigene construct, apoptosis assays RNA biology Medium 30468106
2015 MCL-1 involvement in mitochondrial dynamics is mediated through its two isoforms: increased MCL-1S/L ratio (promoted by splice-switching antisense oligonucleotides) induces mitochondrial hyperfusion in a Drp1-dependent manner and increases mitochondrial calcium accumulation. The balance between MCL-1L and MCL-1S isoforms regulates mitochondrial fusion/fission machinery. Splice-switching antisense oligonucleotides, measurement of mitochondrial morphology, mitochondrial calcium accumulation assays, Drp1-dependence analysis Molecular biology of the cell Medium 26538029
2021 The deubiquitinase USP13 binds to, deubiquitinates, and stabilizes MCL-1 in cervical cancer cells. Depletion of USP13 reduces MCL-1 protein levels and inhibits cell proliferation. USP13 and MCL-1 protein levels correlate in cervical cancer tissue. Co-immunoprecipitation of USP13 with MCL-1, ubiquitination assays, siRNA knockdown, proliferation assays, IHC correlation in tissue Oncogene Medium 33627786
2022 Skp2 stabilizes MCL-1 by competing with the E3 ligase FBW7-mediated MCL-1 ubiquitination. Depletion of Skp2 enhances FBW7-mediated MCL-1 ubiquitination and degradation, increasing irradiation-induced apoptosis. The Skp2/MCL-1 axis controls radioresistance in colorectal cancer. Co-immunoprecipitation, ubiquitination analysis, CRISPR-Cas9 Skp2 knockout, Western blotting, xenograft experiments, flow cytometry Cell death & disease Medium 35301297
2022 Stabilization of MCL-1 by E3 ligase TRAF4 occurs through a TRAF4-Akt-GSK3β signaling axis. TRAF4 promotes Akt K63-mediated ubiquitination and activation; TRAF4 knockout inhibits Akt phosphorylation and upregulates GSK3β activity, leading to increased MCL-1 S159 phosphorylation that disrupts MCL-1 interaction with deubiquitinase JOSD1, thereby promoting MCL-1 ubiquitination and degradation. Co-immunoprecipitation of TRAF4 with Akt and MCL-1, ubiquitination analysis, GSK3β activity assays, phospho-specific Western blotting (MCL-1 S159), TRAF4 knockout, xenograft experiments Cell death & disease Medium 36535926
2021 PP2A phosphatase stabilizes MCL-1 in multiple myeloma cells by dephosphorylating MCL-1 at Ser159 and/or Thr163. PP2A inhibition by okadaic acid increases MCL-1 phosphorylation at these sites and destabilizes MCL-1. The MCL-1 half-life in MM is regulated by counteracting functions of JNK kinase and PP2A phosphatase. Phosphatase siRNA screen, PP2A inhibitor (okadaic acid), phospho-specific Western blotting, combined kinase/phosphatase inhibitor experiments, MCL-1 half-life measurements Cell death & disease Medium 33658484
2017 FBXO4 functions as an E3 ubiquitin ligase for MCL-1, interacting with MCL-1 and promoting its ubiquitination and proteasomal degradation. Knockdown of FBXO4 elevates MCL-1 protein levels and increases cell survival and chemotherapy resistance, while ectopic FBXO4 expression has opposite effects. Co-immunoprecipitation, ubiquitination assays, FBXO4 knockdown and overexpression, Western blotting for MCL-1 protein levels, cell viability assays Cancer gene therapy Medium 28776569
2012 Caveolin-1 (Cav-1) regulates MCL-1 stability through direct protein-protein interaction, preventing MCL-1 ubiquitination and degradation during anoikis. Cav-1-overexpressing cells show elevated MCL-1 and MCL-1-Cav-1 complex, while Cav-1 knockdown reduces MCL-1 and increases its ubiquitination. Co-immunoprecipitation, immunocytochemistry, Cav-1 overexpression and knockdown, ubiquitination assays, anoikis assays American journal of physiology. Cell physiology Medium 22277751
2022 MCL-1 is a master regulator of fatty acid oxidation (FAO) in MCL-1-dependent hematologic cancer cells. FAO regulation by MCL-1 is independent of its anti-apoptotic activity, as demonstrated by metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking an intact apoptotic pathway. Genetic deletion of Mcl-1 results in transcriptional downregulation of FAO pathway proteins, making cells susceptible to glucose withdrawal-triggered cell death even when apoptosis is blocked. Mcl-1 genetic deletion, metabolomic profiling, proteomic profiling, genomic profiling, glucose withdrawal experiments in apoptosis-deficient cells Cell reports High 36198266
2022 MCL-1 suppresses non-selective starvation-induced autophagy but promotes selective autophagy (mitophagy) of dysfunctional mitochondria. MCL-1 interacts with the mitophagy receptor Bnip3, and this interaction increases during mitochondrial stress. MCL-1-mediated mitochondrial clearance is partially dependent on its LC3-interacting regions (LIR motifs), as mutation of LIR sites significantly reduces MCL-1-mediated mitochondrial clearance. Cardiac-specific MCL-1 overexpression, autophagic flux assays, mitophagy assays, co-immunoprecipitation of MCL-1 with Bnip3, LIR motif mutagenesis, mitochondrial depolarization experiments Cells Medium 35563775
2020 The transmembrane domain (TMD) of MCL-1 forms homooligomers in the mitochondrial membrane and competes with full-length MCL-1 for its antiapoptotic function. MCL-1 TMD can also heterooligomerize with the Bok TMD predominantly at the mitochondrial membrane. Coexpression of MCL-1 and Bok TMDs increases ER-mitochondria associated membranes. Cancer-associated somatic mutations in the MCL-1 TMD alter the TMD interaction pattern to enhance MCL-1 antiapoptotic activity. Oligomerization assays, subcellular fractionation, apoptosis assays, mutagenesis of cancer-associated TMD variants, ER-mitochondria contact site analysis Proceedings of the National Academy of Sciences of the United States of America Medium 33093207
2014 STAT3 and MCL-1 are direct interacting partners during embryo implantation, with the interaction regulated by estrogen and progesterone. Association of MCL-1 with STAT3 modulates MCL-1's normal anti-apoptotic activity, resulting in pro-apoptotic effects and decreased cellular invasion in MCF7 cells. MALDI-TOF analysis, far-western analysis, co-localization studies, co-transfection experiments, apoptosis and invasion assays Journal of cell science Low 24481815
2003 During apoptosis, MCL-1 protein levels decline through both caspase-dependent (affecting mRNA) and proteasome-dependent (affecting protein) pathways. Staurosporine reduces MCL-1 mRNA through caspase-dependent transcriptional inhibition of the MCL-1 promoter, while aspirin reduces MCL-1 protein via cap-dependent translation inhibition with eIF2α phosphorylation, without affecting mRNA. Caspase inhibitor (Z-VAD.fmk), proteasome inhibitor (MG132), actinomycin D, luciferase reporter constructs for MCL-1 promoter, IRES-luciferase translation reporter, eIF2α phosphorylation assays, cycloheximide treatment Archives of biochemistry and biophysics Medium 12941295
2013 Notch1 directly controls the MCL-1 promoter through a conserved CSL/RBP-Jκ binding site. Notch1 upregulation in macrophages treated with PPD or infected with BCG correlates with MCL-1 upregulation. Silencing Notch1 decreases MCL-1 protein expression, and gamma-secretase inhibition (blocking Notch processing) reduces both Notch1 and MCL-1 levels with increased apoptosis. Chromatin immunoprecipitation (ChIP) of Notch1 at MCL-1 promoter, gamma-secretase inhibitor experiments, Notch1 siRNA knockdown, promoter sequence analysis, Western blotting and RT-PCR Cellular & molecular immunology Medium 23872918
2018 Phosphorylation of Bim regulates MCL-1 stability and binding specificity. Constitutively phosphorylated Bim stabilizes MCL-1 in RPCI-WM1 cells. Phospho-mimetic and unphosphorylatable Bim mutations result in altered MCL-1 stability and distinct Bim binding patterns to antiapoptotic proteins, linking Bim phosphorylation to enforcement of MCL-1 dependence. Phospho-mimetic and phospho-deficient Bim mutant expression, MCL-1 stability assays, co-immunoprecipitation to assess Bim-MCL-1 binding, cell viability assays The FEBS journal Medium 29775995
2016 During mitotic arrest (taxol treatment), proteasome-mediated MCL-1 degradation occurs independently of APC/C-Cdc20, FBW7, or MULE E3 ubiquitin ligases. MCL-1 is continuously synthesized during mitosis. Blocking proteasome-mediated degradation inhibits taxol-induced mitotic apoptosis in an MCL-1-dependent manner. Overexpression of MCL-1 extends the time from mitotic entry to exit under taxol, while MCL-1 inhibition accelerates mitotic exit, suggesting MCL-1 competes with Cyclin B1 for the proteolysis machinery. Proteasome inhibitor experiments, siRNA knockdown of APC/C-Cdc20/FBW7/MULE, time-lapse microscopy, MCL-1 overexpression and inhibition, Cyclin B1 degradation assays Oncotarget Medium 26769847
2011 A novel 'reverse BH3' (rBH3) binding motif was identified for MCL-1 through phage display screening. rBH3 peptides bind selectively to the BH3-binding groove of MCL-1 over Bcl-xL, with a reverse organization of conserved hydrophobic and acidic residues compared to canonical BH3 sequences. Phage display library screening with Sabutoclax as competitor, NMR spectroscopy, fluorescence polarization displacement assays, alanine scanning The Journal of biological chemistry Medium 21953453
2023 MCL-1 inhibitors (AMG-176 and AZD5991) induce MCL-1 protein stability predominantly through defective MCL-1 ubiquitination via enhanced deubiquitination (through USP9x) and dissociation of MCL-1 from Noxa (leading to Noxa degradation) and from Bak/Bax. Mule E3 ligase is destabilized. ERK-mediated MCL-1 Thr163 phosphorylation partially contributes. WP1130 (global DUB inhibitor) abrogates MCL-1 induction. Protein half-life assays, reverse-phase protein array, Co-IP, phosphorylation analysis, ubiquitination and de-ubiquitination assays in vitro, DUB inhibitor experiments, molecular simulation and modeling Clinical cancer research Medium 36346691

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Mcl-1; the molecular regulation of protein function. FEBS letters 453 20540941
1998 Mcl-1 expression in human neutrophils: regulation by cytokines and correlation with cell survival. Blood 312 9746790
2009 Mcl-1 is a potential therapeutic target in multiple types of cancer. Cellular and molecular life sciences : CMLS 277 19099185
2003 DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells. Genes & development 271 14633975
2021 Targeting MCL-1 in cancer: current status and perspectives. Journal of hematology & oncology 244 33883020
2006 The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages. Blood 239 17062731
2013 Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. Genes & development 220 23788622
2005 Mcl-1. The international journal of biochemistry & cell biology 209 15474972
2012 Delving deeper: MCL-1's contributions to normal and cancer biology. Trends in cell biology 191 23026029
2010 Mcl-1 is essential for germinal center formation and B cell memory. Science (New York, N.Y.) 190 20929728
2020 Targeting MCL-1 in hematologic malignancies: Rationale and progress. Blood reviews 169 32204955
2008 Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage. The Journal of neuroscience : the official journal of the Society for Neuroscience 165 18550749
2011 Targeting Mcl-1 for the therapy of cancer. Expert opinion on investigational drugs 160 21851287
2014 Mcl-1 ubiquitination: unique regulation of an essential survival protein. Cells 156 24814761
2014 Small molecule Mcl-1 inhibitors for the treatment of cancer. Pharmacology & therapeutics 140 25172548
2004 VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis. Blood 131 15217829
2020 Saga of Mcl-1: regulation from transcription to degradation. Cell death and differentiation 128 31907390
2004 Mcl-1 regulation and its role in multiple myeloma. Cell cycle (Georgetown, Tex.) 120 15467463
2009 Mcl-1 is required for melanoma cell resistance to anoikis. Molecular cancer research : MCR 114 19372583
2015 Mcl-1 involvement in mitochondrial dynamics is associated with apoptotic cell death. Molecular biology of the cell 113 26538029
2010 Ubiquitin-independent degradation of antiapoptotic MCL-1. Molecular and cellular biology 107 20385764
2018 MCL-1 inhibition in cancer treatment. OncoTargets and therapy 106 30425521
2019 Recent advances in the development of Mcl-1 inhibitors for cancer therapy. Pharmacology & therapeutics 105 30790641
2022 Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer. Nature communications 99 35449130
2010 Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia. Blood 98 20971952
2008 Mcl-1: a gateway to TRAIL sensitization. Cancer research 98 18381408
2006 Mcl-1: a highly regulated cell death and survival controller. Journal of biomedical science 90 16456709
2007 Anoikis, initiated by Mcl-1 degradation and Bim induction, is deregulated during oncogenesis. Cancer research 86 18006817
2020 Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor. Journal of medicinal chemistry 85 33146521
2004 Regulation of neutrophil apoptosis by Mcl-1. Biochemical Society transactions 85 15157168
2019 Molecular Comprehension of Mcl-1: From Gene Structure to Cancer Therapy. Trends in cell biology 78 31030977
2013 MiR-139 inhibits Mcl-1 expression and potentiates TMZ-induced apoptosis in glioma. CNS neuroscience & therapeutics 78 23551751
2012 Regulation of Mcl-1 by SRSF1 and SRSF5 in cancer cells. PloS one 78 23284704
2011 Mcl-1 ubiquitination and destruction. Oncotarget 74 21608150
2011 Regulation of neutrophil survival/apoptosis by Mcl-1. TheScientificWorldJournal 72 22125448
2002 Tankyrase 1 interacts with Mcl-1 proteins and inhibits their regulation of apoptosis. The Journal of biological chemistry 68 12475993
2015 Multiple myeloma induces Mcl-1 expression and survival of myeloid-derived suppressor cells. Oncotarget 64 25871384
2016 Mcl-1 dynamics influence mitotic slippage and death in mitosis. Oncotarget 63 26769847
2020 Development of Mcl-1 inhibitors for cancer therapy. European journal of medicinal chemistry 62 33333396
2003 Transcriptional and translational control of Mcl-1 during apoptosis. Archives of biochemistry and biophysics 62 12941295
2020 Mcl-1 inhibition overcomes intrinsic and acquired regorafenib resistance in colorectal cancer. Theranostics 60 32724460
2019 Hot-Spots of Mcl-1 Protein. Journal of medicinal chemistry 59 31580668
2010 MCL-1 localizes to sites of DNA damage and regulates DNA damage response. Cell cycle (Georgetown, Tex.) 59 20647761
2017 FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors. Molecular cancer therapeutics 58 28619760
2023 Targeting MCL-1 protein to treat cancer: opportunities and challenges. Frontiers in oncology 56 37601693
2016 Dual modulation of MCL-1 and mTOR determines the response to sunitinib. The Journal of clinical investigation 56 27893461
2017 Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy. The Journal of clinical investigation 54 29227281
2016 Intersection of mitochondrial fission and fusion machinery with apoptotic pathways: Role of Mcl-1. Biology of the cell 54 27234233
2015 Mcl-1 is an important therapeutic target for oral squamous cell carcinomas. Oncotarget 53 26009874
2016 Allosteric inhibition of antiapoptotic MCL-1. Nature structural & molecular biology 52 27159560
2020 MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically. Nature communications 51 32913197
2018 Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents. European journal of medicinal chemistry 51 29407973
2020 AMG-176, an Mcl-1 Antagonist, Shows Preclinical Efficacy in Chronic Lymphocytic Leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 49 31937611
2019 MCL-1 inhibitors - where are we now (2019)? Expert opinion on therapeutic patents 49 31566022
2020 Pairing MCL-1 inhibition with venetoclax improves therapeutic efficiency of BH3-mimetics in AML. European journal of haematology 46 32659848
2021 The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer. Oncogene 45 33627786
2018 Mcl-1 targeting could be an intriguing perspective to cure cancer. Journal of cellular physiology 45 29797573
2014 Bak and Mcl-1 are essential for Temozolomide induced cell death in human glioma. Oncotarget 44 24811082
2022 Skp2 stabilizes Mcl-1 and confers radioresistance in colorectal cancer. Cell death & disease 42 35301297
2016 Mcl-1 inhibitors: a patent review. Expert opinion on therapeutic patents 42 27744724
2018 Regulation of Mcl-1 alternative splicing by hnRNP F, H1 and K in breast cancer cells. RNA biology 41 30468106
2021 Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function. Cell death and differentiation 39 33785871
2012 Caveolin-1 regulates Mcl-1 stability and anoikis in lung carcinoma cells. American journal of physiology. Cell physiology 39 22277751
2020 Mcl-1 and Bok transmembrane domains: Unexpected players in the modulation of apoptosis. Proceedings of the National Academy of Sciences of the United States of America 37 33093207
2011 The expression of Mcl-1 in human cervical cancer and its clinical significance. Medical oncology (Northwood, London, England) 37 21674276
2009 Mcl-1 degradation during hepatocyte lipoapoptosis. The Journal of biological chemistry 37 19734538
2016 Survival control of malignant lymphocytes by anti-apoptotic MCL-1. Leukemia 36 27479182
2019 Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia. Frontiers in oncology 35 31921615
2011 Identification of a novel Mcl-1 protein binding motif. The Journal of biological chemistry 34 21953453
2020 Cotargeting BCL-2 and MCL-1 in high-risk B-ALL. Blood advances 33 32569380
2017 FBXO4 inhibits lung cancer cell survival by targeting Mcl-1 for degradation. Cancer gene therapy 33 28776569
2020 Discovery of a Copper-Based Mcl-1 Inhibitor as an Effective Antitumor Agent. Journal of medicinal chemistry 32 32794745
2017 Promoting Vaginal Distribution of E7 and MCL-1 siRNA-Silencing Nanoparticles for Cervical Cancer Treatment. Molecular pharmaceutics 32 28350964
2021 Mcl-1 Inhibition: Managing Malignancy in Multiple Myeloma. Frontiers in pharmacology 31 34349655
2009 Mcl-1 functions as major epidermal survival protein required for proper keratinocyte differentiation. The Journal of investigative dermatology 31 19037233
2019 Mcl-1 Interacts with Akt to Promote Lung Cancer Progression. Cancer research 30 31662324
2015 Mcl-1 is vital for neutrophil survival. Immunologic research 30 25929430
2015 Mcl-1 is a key regulator of the ovarian reserve. Cell death & disease 30 25950485
2013 Notch signaling regulates expression of Mcl-1 and apoptosis in PPD-treated macrophages. Cellular & molecular immunology 29 23872918
2022 MCL-1 is a master regulator of cancer dependency on fatty acid oxidation. Cell reports 28 36198266
2022 MCL-1 is a clinically targetable vulnerability in breast cancer. Cell cycle (Georgetown, Tex.) 25 35349392
2022 Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage. Cells 25 35563775
2019 CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax. Molecular pharmacology 25 31467029
2020 Sphingosine kinase-2 is overexpressed in large granular lymphocyte leukaemia and promotes survival through Mcl-1. British journal of haematology 24 32124438
2018 Phosphorylation alters Bim-mediated Mcl-1 stabilization and priming. The FEBS journal 24 29775995
2015 AML sensitivity to YM155 is modulated through AKT and Mcl-1. Cancer letters 23 26118775
2016 Dual inhibition of Mcl-1 by the combination of carfilzomib and TG02 in multiple myeloma. Cancer biology & therapy 22 27246906
2014 STAT3 and MCL-1 associate to cause a mesenchymal epithelial transition. Journal of cell science 22 24481815
2011 Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival. BMC cancer 22 21247487
2023 Mechanisms of MCL-1 Protein Stability Induced by MCL-1 Antagonists in B-Cell Malignancies. Clinical cancer research : an official journal of the American Association for Cancer Research 21 36346691
2022 Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance. Cell death & disease 21 36535926
2021 Inhibition of the anti-apoptotic protein MCL-1 severely suppresses human hematopoiesis. Haematologica 21 33241675
2021 Requirement for antiapoptotic MCL-1 during early erythropoiesis. Blood 20 33512417
2018 Repurposing of mTOR Complex Inhibitors Attenuates MCL-1 and Sensitizes to PARP Inhibition. Molecular cancer research : MCR 20 30201826
2017 MCL-1 Is a Key Antiapoptotic Protein in Human and Rodent Pancreatic β-Cells. Diabetes 20 28667119
2015 EGFR signaling defines Mcl⁻1 survival dependency in neuroblastoma. Cancer biology & therapy 20 25756510
2021 Phosphatase PP2A enhances MCL-1 protein half-life in multiple myeloma cells. Cell death & disease 18 33658484
2019 MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma. Oncogene 18 31735913
2019 Photocatalytic proximity labelling of MCL-1 by a BH3 ligand. Communications chemistry 18 33763603
2017 BIRC6 mediates imatinib resistance independently of Mcl-1. PloS one 18 28520795

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