How menin holds the beta cell still: JunD recruits it, with HDAC3, onto the Pbk promoter
also called menin JunD Pbk · Pbk beta cell proliferation · menin HDAC3 islet
In insulin-making cells, a protein called JunD drags menin and a histone-stripping enzyme onto the switch for a growth kinase called Pbk, and keeps that switch off. A menin-blocking drug breaks that grip and the growth kinase comes on.
The same thing, for a scientist
Ma and colleagues define the molecular route from menin to beta-cell proliferation. JunD recruits menin and HDAC3 to the Pbk promoter, reducing histone H3 acetylation and repressing Pbk, a serine/threonine kinase required for high-fat-diet-induced compensatory beta-cell proliferation in vivo (shown with a Pbk kinase-deficient knock-in mouse). Menin inhibitors MI-503 and MI-463 disrupt the menin-JunD co-immunoprecipitation dose-dependently at 30, 100 and 300 nM in HEK293T cells; ChIP in PIME cells, INS-1 cells and mouse primary islets shows reduced menin and HDAC3 occupancy and increased H3 acetylation at the Pbk locus under MI-503; and MI-induced Pbk up-regulation does not occur in Men1-deleted cells, establishing on-target dependence [E1]. This is the same pocket and the same JunD interaction that the endocrine-risk entries in this graph treat as a liability - here it is the mechanism of a proposed benefit.
The chain, step by step
- JunD binds the Pbk promoter and recruits menin and HDAC3 1.
- Histone H3 acetylation at Pbk falls; Pbk transcription is repressed 1.
- High-fat diet raises Pbk in islets; Pbk kinase activity is required for the compensatory beta-cell proliferation that follows (Pbk kinase-dead knock-in mice fail to compensate and their glucose intolerance worsens progressively) 1.
- A menin inhibitor disrupts menin-JunD binding, evicts menin and HDAC3 from the Pbk locus, raises H3 acetylation and de-represses Pbk 1.
- The de-repression is menin-dependent: it does not happen in Men1-null PIME cells 1.
Concentrations, verbatim from the paper1 deeper
Read from the Europe PMC full text of PMC8103087 on 2026-09-19 1:
- Co-IP: MI-503 at 30, 100, 300 nM and MI-463 at 30, 100, 300 nM, dose-dependent loss of menin-JunD binding.
- PIME cells, MI-463 48 h: Pbk mRNA up at 25 nM (p=0.0022), 50 nM (p=0.0479), 100 nM (p=0.0233).
- Mouse primary islets, MI-463 5 days: Pbk mRNA up at 50 and 100 nM; Ki67 mRNA up at 25, 50 and 100 nM.
- Human primary islets (4 donors), MI-503 5 days: PBK mRNA up at 10, 50 and 100 nM (p=0.0036, 0.0024, 0.0073); Ki67 mRNA significant only at 50 nM (p=0.0237).
Provenance note: which paper actually carries the human-islet Ki67 result
This beat was briefed that "MI-503 raises Ki67 in primary human islets at 10-100 nM" on the strength of this paper. The claim is true of the literature but is mis-attributed. The human-islet Ki67 result belongs to Muhammad 2017 (PMID 28270438), which states that ex vivo treatment of both mouse and human pancreatic islets with a menin inhibitor increases Ki67 - see mechanism-menin-prmt5-represses-glp1r-transcription. In this paper the human arm is four donors and the Ki67 mRNA change reaches significance at one concentration (50 nM, p=0.0237) out of three; the robust, dose-graded human readout here is PBK mRNA (10, 50 and 100 nM), and the Ki67 protein immunofluorescence proliferation index was measured in mice, not in human islets. Recorded so that the next reader does not cite the wrong paper for the strongest human-tissue claim in this beat.
Why this belongs in a bite-back beat
interface-menin-jund-pocket and mechanism-jund-release-inverts-to-growth-promotion argue that displacing JunD from menin is the endocrine danger, because JunD without menin flips from growth suppressor to growth promoter. This paper shows the same displacement, at the same nanomolar concentrations, producing a proliferative response in the beta cell - and reports it as therapeutic. Both readings are of the same molecular event. The difference is only whether the resulting proliferation stops. Neither the toxicity entries nor this paper measures that.
| axis | JunD -> menin + HDAC3 -> H3 deacetylation at Pbk promoter -> Pbk repression |
|---|---|
| effector | PBK (PDZ-binding kinase / TOPK) |
| clinical compounds tested | none |
tool compounds
[ "MI-463", "MI-503" ]
active range NM
[ 10, 300 ]
systems
[ "HEK293T", "PIME", "INS-1", "mouse primary islets", "human primary islets (n=4 donors)" ]
- The mechanism that makes a menin inhibitor plausibly good for the islet is identical to the mechanism the toxicity entries say makes it bad for the parathyroid; the drug cannot be steered to one and not the other.
- PBK/TOPK is itself an oncology target in other tumours, so pharmacologically inducing it in a child's islet for months has an unmeasured downside.
- All target-engagement data are tool compounds. If revumenib engages this axis more weakly than MI-463, the benefit story evaporates and only the leukaemia-directed risks remain.
- Do revumenib, ziftomenib and bleximenib evict menin and HDAC3 from the Pbk locus at their clinically achieved plasma concentrations?
- Is PBK de-repression detectable in the blood or in an accessible tissue, so that beta-cell target engagement could be monitored in a treated child?
- Does the proliferation stop when the drug stops? No restoration arm exists in this system.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
JunD recruits menin and HDAC3 to the Pbk promoter to repress it, and menin inhibitors disrupt menin-JunD binding at 30-300 nM and de-repress Pbk in a menin-dependent manner.
Menin-regulated Pbk controls high fat diet-induced compensatory beta cell proliferation. · Ma J, Xing B, Cao Y, He X, et al. · EMBO Molecular Medicine 2021What this evidence cannot show
Co-IP is in transfected HEK293T cells with flag-JunD, not in an endocrine cell at endogenous stoichiometry. ChIP is in PIME and INS-1 lines plus mouse primary islets. The human arm is four donors and three technical replicates. The compounds are tool molecules (MI-463, MI-503), not revumenib, ziftomenib or bleximenib; no clinical menin inhibitor has been tested in this system.
Evidence that argues against this (1)
- The same JunD displacement in leukaemic cells, by quantitative mass spectrometry, liberates JUND onto chromatin where it drives target genes and contributes to menin-inhibitor resistance - so JunD release is not a uniformly benign output of pocket occupancy. See gene-jund in the endocrine beat. Chamberlain CE et al. 2014
JunD is the DNA-tethering partner that brings menin and HDAC3 to the Pbk promoter in the beta cell; the menin-JunD interaction the endocrine beat treats as a liability is the substrate of this benefit
MI-503 and MI-463 disrupt menin-JunD co-IP at 30-300 nM, i.e. the same pocket occupancy, with a proliferative rather than neoplastic readout in islet tissue
The in-vivo glucose and proliferation phenotype is abolished in Pbk kinase-dead knock-in mice, tying it to this axis