The Mdm2 Oncoprotein Interacts with the Cell Fate Regulator Numb

Juven‐Gershon, Tamar; Shifman, Ohad; Unger, Tamar; Elkeles, Adi; Haupt, Ygal; Oren, Moshe

doi:10.1128/mcb.18.7.3974

Cited by 129 publications

(104 citation statements)

References 64 publications

(88 reference statements)

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“…Hence, Numb is segregated to only one daughter cell, enabling this cell to adopt a different fate from that of its sibling. The cell receiving high Numb levels suppresses extrinsic Notch signaling and differentiates, whereas the cell with low Numb levels maintains high Notch1 activity and thus has a stem cell fate (Frise et al 1996;Guo et al 1996;Juven-Gershon et al 1998;Yan et al 2008). Therefore, to further confirm that most cell divisions occur asymmetrically in the lung epithelium and that Numb is preferentially expressed by one daughter cell in mitotic lung epithelial progenitors, we tracked Numb versus Sox9 expression as markers of cells acquiring a differentiated cell fate versus stem/progenitor cell fate, respectively, in daughter cells of mitotic distal lung epithelial cells at the mitotic (M) phase of the cell cycle.…”

Section: Resultsmentioning

confidence: 99%

Numb Expression and Asymmetric versus Symmetric Cell Division in Distal Embryonic Lung Epithelium

El-Hashash

Warburton

2012

J Histochem Cytochem.

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Proper balance between self-renewal and differentiation of lung-specific progenitors is absolutely required for normal lung morphogenesis/regeneration. Therefore, understanding the behavior of lung epithelial stem/progenitor cells could identify innovative solutions for restoring normal lung morphogenesis and/or regeneration. The Notch inhibitor Numb is a key determinant of asymmetric or symmetric cell division and hence cell fate. Yet Numb proximal-distal expression pattern and symmetric versus asymmetric division are uncharacterized during lung epithelial development. Herein, the authors find that the cell fate determinant Numb is highly expressed and asymmetrically distributed at the apical side of distal epithelial progenitors and segregated to one daughter cell in most mitotic cells. Knocking down Numb in MLE15 epithelial cells significantly increased the number of cells expressing the progenitor cell markers Sox9/Id2. Furthermore, cadherin hole analysis revealed that most distal epithelial stem/progenitor cells in embryonic lungs divide asymmetrically; with their cleavage, planes are predicted to bypass the cadherin hole, resulting in asymmetric distribution of the cadherin hole to the daughter cells. These novel findings provide evidence for asymmetric cell division in distal epithelial stem/progenitor cells of embryonic lungs and a framework for future translationally oriented studies in this area.

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Section: Resultsmentioning

confidence: 99%

Numb Expression and Asymmetric versus Symmetric Cell Division in Distal Embryonic Lung Epithelium

El-Hashash

Warburton

2012

J Histochem Cytochem.

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“…These activities of MDM2 are probably related to its interaction with other proteins, including regulators of the cell cycle and cell fate such as MTBP , Numb (Juven-Gershon et al, 1998), the retinoblastoma tumour suppressor protein (pRB) (Hsieh et al, 1999), E2F1/DP1 (Loughran and La Thangue, 2000) and SMAD transcription factors (Yam et al, 1999). E2F-1 has been shown to be susceptible to proteasome-mediated degradation and, like p53, it can be stabilized by various forms of cellular stress (Blattner et al, 1999;O'Connor and Lu, 2000).…”

Section: Regulation By Mdm2mentioning

confidence: 99%

Activation and activities of the p53 tumour suppressor protein

Bálint¹,

Vousden²

2001

Br J Cancer

272

178

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The p53 tumour suppressor protein inhibits malignant progression by mediating cell cycle arrest, apoptosis or repair following cellular stress. One of the major regulators of p53 function is the MDM2 protein, and multiple forms of cellular stress activate p53 by inhibiting the MDM2-mediated degradation of p53. Mutations in p53, or disruption of the pathways that allow activation of p53, seem to be a general feature of all cancers. Here we review recent advances in our understanding of the pathways that regulate p53 and the pathways that are induced by p53, as well as their implications for cancer therapy. © 2001 Cancer Research Campaign http://www.bjcancer.com

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“…85 Mdm2 had been shown to bind NUMB and promote its ubiquitylation and degradation. 86,87 The NUMB-Mdm2 physical and functional interaction has more recently been revisited. The physical interaction has been confirmed at endogenous levels of protein expression.…”

Section: Regulation Of Mdm2-mediated P53 Ubiquitylationmentioning

confidence: 99%

Mdm2-mediated ubiquitylation: p53 and beyond

2009

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The really interesting genes (RING)-finger-containing oncoprotein, Mdm2, is a promising drug target for cancer therapy. A key Mdm2 function is to promote ubiquitylation and proteasomal-dependent degradation of the tumor suppressor protein p53. Recent reports provide novel important insights into Mdm2-mediated regulation of p53 and how the physical and functional interactions between these two proteins are regulated. Moreover, a p53-independent role of Mdm2 has recently been confirmed by genetic data. These advances and their potential implications for the development of new cancer therapeutic strategies form the focus of this review.

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The Mdm2 Oncoprotein Interacts with the Cell Fate Regulator Numb

Cited by 129 publications

References 64 publications

Numb Expression and Asymmetric versus Symmetric Cell Division in Distal Embryonic Lung Epithelium

Numb Expression and Asymmetric versus Symmetric Cell Division in Distal Embryonic Lung Epithelium

Activation and activities of the p53 tumour suppressor protein

Mdm2-mediated ubiquitylation: p53 and beyond

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