Bmi1 directly represses p21Waf1/Cip1 in Shh-induced proliferation of cerebellar granule cell progenitors

Subkhankulova, Tatiana; Zhang, X.; Leung, Carly; Marino, Silvia

doi:10.1016/j.mcn.2010.06.006

Cited by 46 publications

(38 citation statements)

References 45 publications

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“…The tumor suppressive CDKN2A/p14 and the CDKN2A/p14 pathway were ruled out since CDKN2A/p16 levels or CDKN1A levels, the ultimate effector of the CDKN2A/p14 pathway 10,32 did not change in BMI1 siRNA or PTC-209-treated cells. Interestingly in chronic myeloid leukemia cells, PTC-209 treatment induces CCNG2 expression and CCNG2-mediated autophagy.…”

Section: Discussionmentioning

confidence: 99%

“…In normal neural stem cells, targeting BMI1 decreases clonal growth through derepression of CDKN2A/INK4/ARF. 8 Therefore in si-BMI1-or PTC-209-treated cells, CDKN2A/p16 INK4A and CDKN1A/cyclin-dependent kinase inhibitor 1A/ (p21, Cip1) levels, the ultimate effector of the CDKN2A/ p14ARF pathway 10,32 were determined and found unchanged (Fig. S2).…”

Section: Ptc-209 Induces Nonapoptotic Caspase-independent Autophagicmentioning

confidence: 98%

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Inhibition of BMI1 induces autophagy-mediated necroptosis

et al. 2016

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The clonal self-renewal property conferred by BMI1 is instrumental in maintenance of not only normal stem cells but also cancer-initiating cells from several different malignancies that represent a major challenge to chemotherapy. Realizing the immense pathological significance, PTC-209, a small molecule inhibitor of BMI1 transcription has recently been described. While targeting BMI1 in various systems significantly decreases clonal growth, the mechanisms differ, are context-dependent, and somewhat unclear. We report here that genetic or pharmacological inhibition of BMI1 significantly impacts clonal growth without altering CDKN2A/INK4/ARF or CCNG2 and induces autophagy in ovarian cancer (OvCa) cells through ATP depletion. While autophagy can promote survival or induce cell death, targeting BMI1 engages the PINK1-PARK2-dependent mitochondrial pathway and induces a novel mode of nonapoptotic, necroptosis-mediated cell death. In OvCa, necroptosis is potentiated by activation of the RIPK1-RIPK3 complex that phosphorylates its downstream substrate, MLKL. Importantly, genetic or pharmacological inhibitors of autophagy or RIPK3 rescue clonal growth in BMI1 depleted cells. Thus, we have established a novel molecular link between BMI1, clonal growth, autophagy and necroptosis. In chemoresistant OvCa where apoptotic pathways are frequently impaired, necroptotic cell death modalities provide an important alternate strategy that leverage overexpression of BMI1.

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Section: Discussionmentioning

confidence: 99%

Section: Ptc-209 Induces Nonapoptotic Caspase-independent Autophagicmentioning

confidence: 98%

Inhibition of BMI1 induces autophagy-mediated necroptosis

et al. 2016

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“…Bmi1 is a direct target gene of the Hh/Gli pathway and a putative marker of stem/progenitor cells in other organs, [24][25][26] and transient Hh activation preserved Bmi1 expression and the Bmi1 + cell population in irradiated mouse SMGs. 15 To determine whether Bmi1…”

Section: Hh-responsive Cells Do Not Directly Contribute To Regeneratementioning

confidence: 97%

Rescue Effects and Underlying Mechanisms of IntraglandShhGene Delivery on Irradiation-Induced Hyposalivation

et al. 2016

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“…Despite a dosage-dependent increase in Bmi1 via Hh signaling, we were unable to observe a change in Bmi1 with Hh blockade. This may suggest that there are Hhindependent mechanisms that regulate Bmi1 (Subkhankulova et al, 2010). However, an alternate explanation may be offered by the fact that the majority of unsorted population comprises CD133À cells, which possess few Hh receptors and would show indifference to KAADcyclopamine-mediated Hh signaling blockade.…”

Section: Shh Regulates Bmi1 In Medulloblastoma Bticsmentioning

confidence: 99%

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

et al. 2011

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Bmi1 is a key stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including medulloblastoma. Overexpression of Bmi1 promotes cell proliferation and is required for hedgehog (Hh) pathwaydriven tumorigenesis. This study aimed to determine if Sonic hedgehog (Shh) modulates the key stem cell regulatory gene Bmi1 in childhood medulloblastoma brain tumor-initiating cells (BTICs). Although current literature suggests that there is a correlation between Shh pathway genes and Bmi1 expression, it is unclear whether there is indeed a direct regulatory mechanism. To address whether Shh induces expression of Bmi1, stem cell-enriched populations from medulloblastoma cell lines and primary samples were treated with Shh ligand and KAAD-cyclopamine (Shh antagonist). Our data indicate that Bmi1 expression positively correlates with increasing Shh ligand concentrations. Chromatin immunoprecipitation reveals that Gli1 preferentially binds to the Bmi1 promoter, and Bmi1 transcript levels are increased and decreased by Gli1 overexpression and downregulation, respectively. Knockdown experiments of Bmi1 in vitro and in vivo demonstrate that Hh signaling not only drives Bmi1 expression, but a feedback mechanism exists wherein downstream effectors of Bmi1 may, in turn, activate Hh pathway genes. These findings implicate Bmi1 and Hh as mutually indispensable pathways in medulloblastoma BTIC maintenance. Recent molecular characterization of medulloblastoma also reveals that Bmi1 is overexpressed across all subgroups of medulloblastoma, particularly in the most aggressive subtypes. Lastly, despite recent identification of BTIC markers, the molecular characterization of these cell populations remains unclear. In this work, we propose that the BTIC marker CD133 may segregate a cell population with a Hh-receptor phenotype, thus demonstrating a cell-cell interaction between the CD133 þ Hh receptor cells and the CD133À Hh-secreting cells.

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Bmi1 directly represses p21Waf1/Cip1 in Shh-induced proliferation of cerebellar granule cell progenitors

Cited by 46 publications

References 45 publications

Inhibition of BMI1 induces autophagy-mediated necroptosis

Inhibition of BMI1 induces autophagy-mediated necroptosis

Rescue Effects and Underlying Mechanisms of IntraglandShhGene Delivery on Irradiation-Induced Hyposalivation

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

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