Hedgehog and PI-3 kinase signaling converge on Nmyc1 to promote cell cycle progression in cerebellar neuronal precursors

Kenney, Anna Marie; Widlund, Hans R.; Rowitch, David H.

doi:10.1242/dev.00891

Cited by 198 publications

(214 citation statements)

References 55 publications

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“…Cultures grown in 6-well dishes were lysed with radioimmunoprecipitation assay (RIPA) buffer (150 mM NaCl, 1% NP- 40 Cell counting and statistical analysis. Cell counting was calculated as the percentage of positive cells (BrdU, HuC/D, etc.)…”

Section: Antibodies and Chemicals (I) Mouse Monoclonal Antibodiesmentioning

confidence: 99%

MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors

Berenguer

Herrera

Vuolo

et al. 2013

Molecular and Cellular Biology

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During cerebellum development, Sonic hedgehog (Shh)-induced proliferation of cerebellar granular neuronal precursors (CGNPs) is potently inhibited by bone morphogenetic proteins (BMPs). We have previously reported the upregulation of TIEG-1 and Mash1, two antimitotic factors that modulate MYCN transcription and N-Myc activity, in response to BMP2. To gain further insight into the BMP antimitotic mechanism, we used microRNA (miRNA) arrays to compare the miRNAs of CGNPs proliferating in response to Shh with those of CGNPs treated with Shh plus BMP2. The array analysis revealed that miRNA 11 (miR-22) levels significantly increased in cells treated with BMP2. Additionally, in P7 mouse cerebellum, miR-22 distribution mostly recapitulated the combination of BMP2 and BMP4 expression patterns. Accordingly, in CGNP cultures, miR-22 overexpression significantly reduced cell proliferation, whereas miR-22 suppression diminished BMP2 antiproliferative activity. In contrast to BMP2, miR-22 did not induce neural differentiation but instead significantly increased cell cycle length. Consistent with the central role played by N-myc on CGNP proliferation, Max was revealed as a direct target of miR-22, and miR-22 expression caused a significant reduction of Max protein levels and N-myc/Max-dependent promoter activity. Therefore, we conclude that, in addition to the previously described mechanisms, miR-22 plays a specific role on downstream BMPs through cerebellum growth.

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Section: Antibodies and Chemicals (I) Mouse Monoclonal Antibodiesmentioning

confidence: 99%

MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors

Berenguer

Herrera

Vuolo

et al. 2013

Molecular and Cellular Biology

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“…HH ligands are well-known mitogens for neuronal precursors and lung mesenchyme, as well as for several other cell types (Pepicelli et al, 1998;Kenney et al, 2004). Moreover, given that reductions in Vegf-A expression and deletion of HIF1␣ result in defects in vascular development and deficits in tissue growth (Ferrara et al, 1996;Ryan et al, 1998;Schipani et al, 2001;Zelzer et al, 2004), one might expect that ventricular growth would be dependent on the development of a vascular supply.…”

Section: Probing the Role Of Cardiomyocyte Proliferation During Midgementioning

confidence: 99%

“…We have also shown that Hedgehog (HH) signaling acts downstream of FGF in the coronary vasculogenic pathway controlling the expression of VEGF ligands (Lavine et al, 2006). Given the extensive data highlighting the ability of both FGF and HH signaling to regulate multiple cellular processes, including cell proliferation, migration, differentiation, and vascular growth (Pepicelli et al, 1998;Kenney et al, 2004;Eswarakumar et al, 2005), it is unclear which component(s) of this FGF-dependent pathway is responsible for the coordinate regulation of myocardial growth and coronary vascular development.…”

Section: Introductionmentioning

confidence: 99%

Novel tool to suppress cell proliferation in vivo demonstrates that myocardial and coronary vascular growth represent distinct developmental programs

Lavine

Schmid

Smith

et al. 2008

Developmental Dynamics

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Cell proliferation, differentiation, and vascular growth are coordinated processes that are essential for embryonic development, tissue repair, and disease pathogenesis. Of interest, whether these critical processes are dependent upon each other has not been thoroughly explored. We have generated mice that conditionally express the cell cycle inhibitor p27 Kip1 , following Cre-mediated recombination, as a tool to separate tissue proliferation from other cellular processes. Using the embryonic heart as a model, we show that myocardial proliferation and coronary development are genetically separable processes. Forced expression of p27, in both a wild-type and in a genetically sensitized background, resulted in ventricular hypoplasia without having any substantial effects on coronary development. We further demonstrate that Hedgehog signaling, which is essential for coronary vascular growth, does not control myocardial proliferation. Together, these studies strongly suggest that myocardial cell proliferation and coronary development are genetically separable programs exemplifying one of the many potential uses of this genetic tool. Developmental Dynamics 237:713-724, 2008.

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“…Active GSK3b normally phosphorylates MYC at the threonine 58 (Thr58) residue, which facilitates the ubiquitinproteasome degradation of MYC protein. PI3K inhibition thus decreases MYC protein stability by releasing GSK3b from AKTmediated inactivation and therefore promoting MYC Thr58 phosphorylation and subsequent degradation (28)(29)(30)(31). Indeed, pharmacologic inhibition of the PI3K pathway is able to induce cell death in PTEN-deficient DLBCL cells as a result of MYC downregulation (32).…”

Section: Introductionmentioning

confidence: 99%

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

Sun

Atoyan

Borek

et al. 2017

Molecular Cancer Therapeutics

117

100

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Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYCdriven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in "double-hit" (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD-NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYCdependent cancers.

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Hedgehog and PI-3 kinase signaling converge on Nmyc1 to promote cell cycle progression in cerebellar neuronal precursors

Cited by 198 publications

References 55 publications

MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors

MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors

Novel tool to suppress cell proliferation in vivo demonstrates that myocardial and coronary vascular growth represent distinct developmental programs

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

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