Combined inhibition of menin-MLL interaction and TGF-β signaling induces replication of human pancreatic beta cells

Pahlavanneshan, Saghar; Behmanesh, Mehrdad; Oropeza, Daniel; Furuyama, Kenichiro; Tahamtani, Yaser; Basiri, Mohsen; Herrera, Pedro Luis; Baharvand, Hossein

doi:10.1016/j.ejcb.2020.151094

Cited by 8 publications

(6 citation statements)

References 26 publications

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“…Pregnancy-induced β-cell expansion is coupled with decreased expression of the histone-associated scaffolding protein Menin1, which has been shown to be sufficient to inhibit p27 KIP1 expression (Rieck & Kaestner, 2010). Furthermore, small molecule mediated Menin1 inhibition has been shown to induce β-cell proliferation by downregulating p27 KIP1 expression (Pahlavanneshan et al, 2020). Menin1 has also been shown to bind HDAC1 (Kim, Lee, Cho, Liu, & Youn, 2003).…”

Section: Discussionmentioning

confidence: 99%

Decreased proliferation of aged rat beta cells corresponds with enhanced expression of the cell cycle inhibitor p27^KIP1

Aitken

Crabtree

Jensen

et al. 2021

Biology of the Cell

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Background: Over 400 million people are diabetic. Type 1 and type 2 diabetes are characterized by decreased functional β-cell mass and, consequently, decreased glucose-stimulated insulin secretion. A potential intervention is transplantation of β-cell containing islets from cadaveric donors. A major impediment to greater application of this treatment is the scarcity of transplant-ready β-cells. Therefore, inducing β-cell proliferation ex vivo could be used to expand functional β-cell mass prior to transplantation. Various molecular pathways are sufficient to induce proliferation of young β-cells; however, aged β-cells are refractory to these proliferative signals. Given that the majority of cadaveric donors fit an aged demographic, defining the mechanisms that impede aged β-cell proliferation is imperative. Results:We demonstrate that aged rat (5-month-old) β-cells are refractory to mitogenic stimuli that otherwise induce young rat (5-week-old) β-cell proliferation. We hypothesized that this change in proliferative capacity could be due to differences in cyclin-dependent kinase inhibitor expression. We measured levels of p16 INK4a , p15 INK4b , p18 INK4c , p19 INK4d , p21 CIP1 , p27 KIP1 and p57 KIP2 by immunofluorescence analysis. Our data demonstrates an age-dependent increase of p27 KIP1 in rat β-cells by immunofluorescence and was validated by increased p27 KIP1 protein levels by western blot analysis. Interestingly, HDAC1, which modulates the p27 KIP1 promoter acetylation state, is downregulated in aged rat islets. These data demonstrate increased p27 KIP1 protein levels at 5 months of age, which may be due to decreased HDAC1 mediated repression of p27 KIP1 expression. Significance: As the majority of transplant-ready β-cells come from aged donors, it is imperative that we understand why aged β-cells are refractory to mitogenic stimuli. Our findings demonstrate that increased p27 KIP1 expression occurs early in β-cell aging, which corresponds with impaired β-cell proliferation. Furthermore, the correlation between HDAC1 and p27 levels suggests that pathways that activate HDAC1 in aged β-cells could be leveraged to decrease p27 KIP1 levels and enhance β-cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Decreased proliferation of aged rat beta cells corresponds with enhanced expression of the cell cycle inhibitor p27^KIP1

Aitken

Crabtree

Jensen

et al. 2021

Biology of the Cell

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“…Recently, Hua’s group has demonstrated that menin–MLL inhibitors can induce degradation of the menin protein in MLL-FP leukemia cells via the ubiquitin-proteasome pathway. , This observation suggests that small molecule degraders of menin can be optimized, with this approach demonstrating more potency than reversible or irreversible inhibitors. In future, the development of the menin degraders via inducing the degradation of the menin protein may be an attractive treatment strategy. ,− …”

Section: Discussionmentioning

confidence: 99%

Recent Progress of Small Molecule Menin–MLL Interaction Inhibitors as Therapeutic Agents for Acute Leukemia

et al. 2021

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Mixed lineage leukemia (MLL) gene rearrangements are associated with acute leukemia. The protein menin is regarded as a critical oncogenic cofactor of the resulting MLL fusion proteins in acute leukemia. A direct interaction between menin and the MLL amino terminal sequences is necessary for MLL fusion protein-mediated leukemogenesis. Thus, inhibition of the interaction between menin and MLL has emerged as a novel therapeutic strategy. Recent improvements in structural biology and chemical reactivity have promoted the design and development of selective and potent menin–MLL interaction inhibitors. In this Perspective, different classes of menin–MLL interaction inhibitors are comprehensively summarized. Further research potential, challenges, and opportunities in the field are also discussed.

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“…Transiently knockdown of MEN1 caused a significant down-regulation of CDKN1A and TP53 transcripts, as well as after treatment with staurosporine, proving a direct correlation between MEN1 and the master regulators of cell fate as previously found in gamma-irradiated rat insulinoma cells where, MEN1 mutated variants lowered the apoptotic response [ 17 ]. Additional findings evidenced that the treatment with menin-MLL inhibitor caused the restoration of proliferation mediated by suppression of CDKN1A , CDKN1B and CDKN2C in human pancreatic beta cells [ 18 ]. Furthermore, the knockdown of MEN1 was responsible for the down-regulation of caspase 8 activity in human insulinoma cells and human pancreatic stellate cells.…”

Section: Discussionmentioning

confidence: 99%

Exploring the MEN1 dependent modulation of caspase 8 and caspase 3 in human pancreatic and murine embryo fibroblast cells

et al. 2021

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MEN1 mutation causes pancreatic neuroendocrine neoplasia and benign malignancies of the parathyroid, the adrenal cortex and pituitary gland. The transcriptional activity of its product menin promotes the expression of genes deputed to several cellular mechanism including cell death. Here, we focused on its implication in the activation of the initiator and executioner caspases after staurosporine mediated cell death in 2D and 3D human and murine cell models. The administration of staurosporine, a well-known inducer of apoptotic cell death, caused a significant reduction of BON1, QGP1 and HPSC2.2 cell viability. The transient knockdown of MEN1, performed by using a specific siRNA, caused a significant down-regulation of CDKN1A and TP53 transcripts. The treatment with 1 µM of staurosporine caused also a significant down-regulation of MEN1 and was able to restore the basal expression of TP53 only in QGP1 cells. Transient or permanent MEN1 inactivation caused a decrease of caspase 8 activity in BON1, HPSC2.2 cells and MEN1−/− MEFs treated with staurosporine. Caspase 3/7 activity was suppressed after administration of staurosporine in MEN1 knocked down HPSC2.2 and MEN1−/− MEFs as well. The cleaved caspase 8 and caspase 3 decreased in human cells after MEN1 knockdown and in MEN1−/− MEFs. The treatment with staurosporine caused a reduction of the size of MEN1+/+ MEFs spheroids. Instead, MEN1−/− MEFs spheroids did not show any significant reduction of their size. In conclusion, MEN1 controls the activity of the initiator caspase 8 and the executioner caspase 3 in human and murine cells. Restoring of a functional MEN1 and interfering with the apoptotic mechanism could represent a future strategy for the treatment of MEN1-related malignancies.

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Combined inhibition of menin-MLL interaction and TGF-β signaling induces replication of human pancreatic beta cells

Cited by 8 publications

References 26 publications

Decreased proliferation of aged rat beta cells corresponds with enhanced expression of the cell cycle inhibitor p27^KIP1

Decreased proliferation of aged rat beta cells corresponds with enhanced expression of the cell cycle inhibitor p27^KIP1

Recent Progress of Small Molecule Menin–MLL Interaction Inhibitors as Therapeutic Agents for Acute Leukemia

Exploring the MEN1 dependent modulation of caspase 8 and caspase 3 in human pancreatic and murine embryo fibroblast cells

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Combined inhibition of menin-MLL interaction and TGF-β signaling induces replication of human pancreatic beta cells

Cited by 8 publications

References 26 publications

Decreased proliferation of aged rat beta cells corresponds with enhanced expression of the cell cycle inhibitor p27KIP1

Decreased proliferation of aged rat beta cells corresponds with enhanced expression of the cell cycle inhibitor p27KIP1

Recent Progress of Small Molecule Menin–MLL Interaction Inhibitors as Therapeutic Agents for Acute Leukemia

Exploring the MEN1 dependent modulation of caspase 8 and caspase 3 in human pancreatic and murine embryo fibroblast cells

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Decreased proliferation of aged rat beta cells corresponds with enhanced expression of the cell cycle inhibitor p27^KIP1

Decreased proliferation of aged rat beta cells corresponds with enhanced expression of the cell cycle inhibitor p27^KIP1