The Mad Side of the Max Network: Antagonizing the Function of Myc and More

Rottmann, Sabine; Lüscher, Bernhard

doi:10.1007/3-540-32952-8_4

Cited by 69 publications

(92 citation statements)

References 250 publications

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“…Depending on the cell system used, it has been observed that an excess of ectopic Max could either enhance or inhibit Nmyc activity. Whereas N-myc appears to interact exclusively with Max, Max is less selective, as it binds to members of the Mad family, which function as transcriptional repressors (26,28). Therefore, we studied whether miR-22 modulates N-myc-dependent transcriptional activity.…”

Section: Mir-22 Expression Is Induced By Two Independent Antiprolifermentioning

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: Mir-22 Expression Is Induced By Two Independent Antiprolifermentioning

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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“…Specifically, IKK␣ is required for expression of 2 negative regulators of c-Myc transcription and activity, Mad1 and Ovol1, both of which regulate cell cycle exit keratinocyte differentiation (22,27). Mad1 is a direct binding partner of the Max protein, thereby disrupting Myc:Max oligomers and contributing to down-regulation of c-Myc transcriptional activity, whereas Ovol1 represses c-Myc expression through association with its promoter (22,28). As suggested by ChIP experiments, IKK␣ may serve as a direct coactivator of Ovol1 and Mad1 transcription as it is recruited to their promoters upon TGF-␤ stimulation.…”

Section: The Tumor Suppressor Activity Of Ikk␣ Is Dependent On Its Numentioning

confidence: 99%

The tumor suppressor activity of IKKα in stratified epithelia is exerted in part via the TGF-β antiproliferative pathway

Marinari¹,

Moretti²,

Botti³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The transforming growth factor type ␤-1 (TGF-␤) signaling pathway is a major tumor suppressor during early carcinogenesis, and its growth-suppressive activity is commonly lost during early tumor progression. I B kinase ␣ (IKK␣) also acts as a tumor suppressor in stratified epithelia, and its expression and nuclear localization are progressively down-regulated during malignant progression of squamous cell carcinoma (SCC) and acquisition of an invasive phenotype. A critical role for IKK␣ in TGF-␤ signaling in stratified epithelia was identified recently during normal keratinocyte differentiation, and both IKK␣ and components of the TGF-␤ signaling pathway are required for induction of antiproliferative Myc antagonists in such cells. We now describe that the interaction between IKK␣ and the TGF-␤ signaling pathway is also important in a subset of SCCs. In SCCs that are unable to shuttle IKK␣ to the nucleus, defective TGF-␤-induced growth arrest was rescued by introduction of a constitutively nuclear IKK␣ variant. These results suggest that the tumor-suppressive activity of IKK␣ in stratified epithelia may be exerted in part via the TGF-␤ signaling pathway.squamous cell carcinoma ͉ Myc ͉ skin cancer

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“…phosphorylation ͉ RSK ͉ S6K1 ͉ ubiquitination ͉ proliferation M ad1 (encoded by the gene mxd1), a member of the Myc/Mad/Max family known as bHLH/LZip proteins (1,2), is recognized as an important cellular antagonist of Myc (1,2). Mad1 antagonizes Myc function by recruiting Max and the mSin3 repressor complex to Myc-responsive elements, directly competing with the Myc-Max dimer for access to transcriptional sites (1,2).…”

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confidence: 99%

“…Mad1 antagonizes Myc function by recruiting Max and the mSin3 repressor complex to Myc-responsive elements, directly competing with the Myc-Max dimer for access to transcriptional sites (1,2). The half-life of Mad1 protein, like that of Myc protein, is very short (1), and the levels of Mad1 are tightly regulated during cell proliferation and differentiation (2).…”

mentioning

confidence: 99%

Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1

Zhu

Blenis

Yuan

2008

Proc. Natl. Acad. Sci. U.S.A.

202

161

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Mad1, a member of the Myc/Max/Mad family, suppresses Mycmediated transcriptional activity by competing with Myc for heterodimerization with its obligatory partner, Max. The expression of Mad1 suppresses Myc-mediated cell proliferation and transformation. The levels of Mad1 protein are generally low in many human cancers, and Mad1 protein has a very short half-life. However, the mechanism that regulates the turnover of Mad1 protein is poorly understood. In this study, we showed that Mad1 is a substrate of p90 ribosomal kinase (RSK) and p70 S6 kinase (S6K). Both RSK and S6K phosphorylate serine 145 of Mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of Mad1 accelerates the ubiquitination and degradation of Mad1 through the 26S proteasome pathway, which in turn promotes the transcriptional activity of Myc. Our study provides a direct link between the growth factor signaling pathways regulated by PI3 kinase/Akt and MAP kinases with Myc-mediated transcription.

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The Mad Side of the Max Network: Antagonizing the Function of Myc and More

Cited by 69 publications

References 250 publications

MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors

MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors

The tumor suppressor activity of IKKα in stratified epithelia is exerted in part via the TGF-β antiproliferative pathway

Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1

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