Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-ERK MAPK cascade

Bain, Gretchen; Cravatt, Celia B.; Loomans, Cindy J.M.; Alberola‐Ila, José; Hedrick, Stephen M.; Murre, Cornelis

doi:10.1038/84273

Cited by 250 publications

(272 citation statements)

References 51 publications

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“…Previous studies reporting CCK2 receptor activation of the MAPK pathway and the regulation of Id3 expression by this pathway support our data. 28,29 Thus, Id3 was identified as a new target of CCK2 receptor during this study.…”

Section: Cancer Cell Biologymentioning

confidence: 88%

Id3 modulates cellular localization of bHLH Ptf1‐p48 protein

Dufresne¹,

Clerc²,

Dieng³

et al. 2010

Intl Journal of Cancer

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Ptf1-p48 is a pancreas-specific bHLH transcriptional protein, which, in the normal adult pancreas, shows a restricted expression in acinar cells where it is predominantly localized in the nucleus and activates the transcription of exocrinespecific genes. Ptf1-p48 partners with two proteins to form the PTF1 active complex: a bHLH E-protein and suppressor of hairless RBP-J. Cytoplasmic mislocalization of Ptf1-p48 has been reported in pancreatic pathologies, suggesting its contribution in the early steps of pancreatic carcinogenesis. The aim of the our work was to elucidate the mechanisms regulating Ptf1-p48 subcellular localization. We hypothesized a role of Id proteins acting in a dominant-negative fashion by heterodimerizing with bHLH proteins. We reproduced Ptf1-p48 cytoplasmic mislocalization in acinar AR4-2J cells and demonstrated that a proliferative signal elicited by gastrin leads to increases in Id3 protein expression and levels of Id3/E47 and Id3/Ptf1-p48 interactions, and a decrease in the level of E47/Ptf1-p48 interaction. By contrast, Id3 silencing reversed the cytoplasmic mislocalization of Ptf1-p48 induced by gastrin. As E47 is responsible for the nuclear import of the PTF1 complex, disruption of this complex via Id3 interactions with both E47 and Ptf1-p48 appears to induce cytoplasmic mislocalization of Ptf1-p48. We then found that Ptf1-p48 is either absent or mislocalized in the cytoplasm and Id3 is overexpressed in human and murine pancreatic preneoplastic lesions. Our data provide novel insight into the regulation of Ptf1-p48 function and provide evidence that Ptf1-p48 cytoplasmic mislocalization and Id3 overexpression are early events in pancreatic cancer progression.Pancreatic cancer is a devastating disease with an overall 5-year survival of less than 5%. It is often not diagnosed until after the cancer has metastasized and therefore becomes very challenging to treat. During the last 10 years, the precursor lesions to invasive pancreatic cancer have been defined. 1 Pancreatic intraepithelial neoplasia (PanIN) are by far the most common of these lesions and are thought to initiate in the small ducts of the pancreas. PanIN have been validated by murine models that recapitulate the histologic progression hypothesized to occur in humans. These genetically engineered mouse models direct the endogenous expression of mutant KrasG12D to progenitor cells or acinar and centroacinar cells of the mouse pancreas. [2][3][4] Careful examination of the pathologic changes in these models suggests that, in addition to ductal cells, centroacinar cells and/or acinar cells can give rise to PanIN. 5 Lineage tracing studies with reporter mice confirmed that ductal elements can have an acinar histogenesis. They demonstrated that PanIN lesions are derivatives of differentiated acinar cells in response to chronic injury or when a mutant endogenous KrasG12D allele is expressed from its endogenous promoter in acinar cells. 3,4,6 In addition to these results from the mouse models, it has been demonstrated that acinar cel...

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Section: Cancer Cell Biologymentioning

confidence: 88%

Id3 modulates cellular localization of bHLH Ptf1‐p48 protein

Dufresne¹,

Clerc²,

Dieng³

et al. 2010

Intl Journal of Cancer

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“…In this manner, Id gene products enhance TCR-mediated responses by attenuating E protein activity. Recent data from Bain et al (35) have positioned ERK MAP kinase signaling and Id3 gene regulation in a common pathway . They also show that PD98059 inhibits Id3 gene induction in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Duration and Strength of Extracellular Signal-Regulated Kinase Signals Are Altered During Positive Versus Negative Thymocyte Selection

Mariathasan

Zakarian

Bouchard

et al. 2001

The Journal of Immunology

106

100

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During thymocyte development, high-affinity/avidity TCR engagement leads to the induction of negative selection and apoptosis, while lower TCR affinity-avidity interactions lead to positive selection and survival. To elucidate how these extracellular interactions are translated into intracellular signals that distinguish between positive and negative selection, we developed a culture system in which naive double-positive thymocytes were either induced to differentiate along the CD8+ lineage pathway or were triggered for clonal deletion. Using this system, we show that sustained low level activation of extracellular signal-regulated kinases (ERKs) promotes positive selection, whereas strong but transient ERK activation is coupled with negatively selecting stimuli. Importantly, similar ERK activation profiles were demonstrated during positive selection for strong agonist ligands presented at low concentrations or weak agonist ligands. This is consistent with the affinity/avidity model and a role for strong or weak agonists during positive selection. Surprisingly, the addition of a pharmacological inhibitor which blocks ERK activation prevented the induction of negative selection. These data suggest that the duration and strength of the TCR signal is involved in discriminating between positive and negative selection.

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“…Both probes were purified over a G-25-50 Sepharose column. The sequence of the μE5 probe was: 5′-TCG-AAG-AAC-ACC-TGC-AGC-AGC-T-3′ (present in the IgH intronic enhancer) (Bain et al, 2001). …”

Section: Preparation Of the Dna Probesmentioning

confidence: 99%