Myc regulates keratinocyte adhesion and differentiation via complex formation with Miz1

Gebhardt, Anneli; Frye, Michaela; Herold, Steffi; Benitah, Salvador Aznar; Braun, Kristin M.; Samans, Birgit; Watt, Fiona M.; Elsässer, Hans–Peter; Eilers, Martin

doi:10.1083/jcb.200506057

Cited by 103 publications

(123 citation statements)

References 47 publications

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“…41,42 Most notably, repression of these genes has already been shown to depend on association with MIZ1. 43 Thus, it is tempting to speculate that MYC/MIZ1-dependent repression of the gene expression programs reported here could simultaneously represent an inbuilt fail-safe mechanism to prevent expansion of mammary stem cells with oncogenic MYC. (Fig.…”

Section: Discussionmentioning

confidence: 99%

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

et al. 2016

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Apoptosis caused by deregulated MYC expression is a prototype example of intrinsic tumor suppression. However, it is still unclear how supraphysiological MYC expression levels engage specific sets of target genes to promote apoptosis. Recently, we demonstrated that repression of SRF target genes by MYC/MIZ1 complexes limits AKT-dependent survival signaling and contributes to apoptosis induction. Here we report that supraphysiological levels of MYC repress gene sets that include markers of basal-like breast cancer cells, but not luminal cancer cells, in a MIZ1-dependent manner. Furthermore, repressed genes are part of a conserved gene signature characterizing the basal subpopulation of both murine and human mammary gland. These repressed genes play a role in epithelium and mammary gland development and overlap with genes mediating cell adhesion and extracellular matrix organization. Strikingly, acute activation of oncogenic MYC in basal mammary epithelial cells is sufficient to induce luminal cell identity markers. We propose that supraphysiological MYC expression impacts on mammary epithelial cell identity by repressing lineage-specific target genes. Such abrupt cell identity switch could interfere with adhesiondependent survival signaling and thus promote apoptosis in pre-malignant epithelial tissue.

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Section: Discussionmentioning

confidence: 99%

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

et al. 2016

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“…In both cases, the MYC-and MIZ-1-binding sites overlap the transcriptional start site. Binding of the MYC/MIZ-1 complex has little effect on the basal expression of either gene, but blocks their induction by antimitogenic stimuli (Warner et al 1999;Gebhardt et al 2006). Association with MIZ-1 is critical for repression of p15Ink4b by MYC in response to TGF-b both in a tissue culture model and in vivo (Gebhardt et al 2006;van Riggelen et al 2010).…”

Section: Transcriptional Repression By Myc Via Interaction With Miz-1mentioning

confidence: 99%

“…Binding of the MYC/MIZ-1 complex has little effect on the basal expression of either gene, but blocks their induction by antimitogenic stimuli (Warner et al 1999;Gebhardt et al 2006). Association with MIZ-1 is critical for repression of p15Ink4b by MYC in response to TGF-b both in a tissue culture model and in vivo (Gebhardt et al 2006;van Riggelen et al 2010). Similarly, MYC inhibits expression of p21Cip1 in response to DNA damage and to inducers of differentiation in culture via MIZ-1 (Seoane et al 2002;Wu et al 2003).…”

Section: Transcriptional Repression By Myc Via Interaction With Miz-1mentioning

confidence: 99%

“…A second group of genes targeted by MYC/ MIZ-1 complexes are cell-adhesion molecules, most notably integrins (Gebhardt et al 2006). Repression of integrin expression by MYC has been linked to the exit of hematopoietic and skin stem cells from their niches (Waikel et al 2001;Wilson et al 2004), the idea being that the transition from a relatively quiescent cell to a rapidly proliferating transient amplifying cell involves severing of interactions with the stem cell niche.…”

Section: Transcriptional Repression By Myc Via Interaction With Miz-1mentioning

confidence: 99%

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The Role of MIZ-1 in MYC-Dependent Tumorigenesis

Wiese

Walz

Eyß

et al. 2013

Cold Spring Harbor Perspectives in Medicine

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“…For this test, we used Myc V394D knock-in mice, in which c-Myc is unable to interact with Miz-1 owing to a mutation in its helix-loop-helix domain, but can still dimerize with Max (14,27). As expected, stimulation of both Rag1 −/− × Myc V394D and Rag1 −/− thymocytes with αCD3 led to full differentiation of DN3 cells to the DN4 stage (Fig.…”

Section: Ablation Of Trp53mentioning

confidence: 99%

Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination

Rashkovan

Vadnais

Ross

et al. 2014

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

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To be effective, the adaptive immune response requires a large repertoire of antigen receptors, which are generated through V(D)J recombination in lymphoid precursors. These precursors must be protected from DNA damage-induced cell death, however, because V(D)J recombination generates double-strand breaks and may activate p53. Here we show that the BTB/POZ domain protein Miz-1 restricts p53-dependent induction of apoptosis in both pro-B and DN3a pre-T cells that actively rearrange antigen receptor genes. Miz-1 exerts this function by directly activating the gene for ribosomal protein L22 (Rpl22), which binds to p53 mRNA and negatively regulates its translation. This mechanism limits p53 expression levels and thus contains its apoptosis-inducing functions in lymphocytes, precisely at differentiation stages in which V(D)J recombination occurs.T he development of T lymphocytes starts with early thymic progenitors (ETPs) that first enter the thymus after transiting through the bloodstream from the bone marrow. These progenitor cells differentiate through four CD4 − CD8 − double-negative stages of development (DN1-4) before becoming first CD4 + CD8 + double-positive (DP) cells and then either CD4 + or CD8 + single positive T cells. The four DN subsets are differentiated based on their expression of the cell surface markers CD44 and CD25. Cells at the DN3 stage (CD44 − CD25 + ) are fully committed to the T cell lineage and require signaling through cytokine receptors and Notch1 to survive (1). This DN3 population can be further subdivided into DN3a and DN3b based on their size and CD27 surface expression.Importantly, DN3a cells (FSC lo CD27 lo ) actively rearrange the genes encoding the T cell receptor β (TCRβ) chain through V(D)J recombination (1-3). Those DN3a cells that do not productively rearrange the TCRβ locus on both alleles are eliminated by apoptosis. In contrast, cells that productively rearrange their TCRβ chain genes are selected and become DN3b cells (FSC hi CD27 hi ), which express a pre-T cell receptor (pre-TCR), a heterodimer between the TCRβ chain and a pTα chain. DN3b cells grow in size, owing in part to increased metabolic activity (4), and give rise to the (CD44 − CD25 − ) DN4 subset, which in turn rapidly expands to produce CD4 + CD8 + DP cells.

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Myc regulates keratinocyte adhesion and differentiation via complex formation with Miz1

Cited by 103 publications

References 47 publications

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

The Role of MIZ-1 in MYC-Dependent Tumorigenesis

Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination

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