TAp73α Increases p53 Tumor Suppressor Activity in Thyroid Cancer Cells via the Inhibition of Mdm2-Mediated Degradation

Malaguarnera, Roberta; Vella, Veronica; Pandini, Giuseppe; Sanfilippo, M.; Pezzino, V.; Vigneri, Riccardo; Frasca, Francesco

doi:10.1158/1541-7786.mcr-07-0005

Cited by 23 publications

(19 citation statements)

References 64 publications

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“…In this scenario, the functional interactions among p53 family members may be either synergistic or antagonistic with respect to tumor suppression. This is in line with previous reports showing that, in different thyroid cancer models, co-expression of p53 and TAp73α may alternatively result in TAp73α down-regulation [62] or stronger p53 tumor suppressor activity [73]. In the latter case, TAp73α inhibits MDM2-mediated p53 protein degradation by reducing MDM2 binding to p53 and by directly antagonizing p53 activity on the MDM2 promoter (Figure 4B).…”

Section: The P53 Protein Familysupporting

confidence: 92%

New Insights in Thyroid Cancer and p53 Family Proteins

Manzella

Stella

Pennisi

et al. 2017

IJMS

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Thyroid cancers are common endocrine malignancies that comprise tumors with different clinical and histological features. Indeed, papillary and follicular thyroid cancers are slow-growing, well-differentiated tumors, whereas anaplastic thyroid cancers are undifferentiated neoplasias that behave much more aggressively. Well-differentiated thyroid carcinomas are efficiently cured by surgery and radioiodine, unlike undifferentiated tumors that fail to uptake radioactive iodine and are usually resistant to chemotherapy. Therefore, novel and more effective therapies for these aggressive neoplasias are urgently needed. Whereas most genetic events underlying the pathogenesis of well-differentiated thyroid cancers have been identified, the molecular mechanisms that generate undifferentiated thyroid carcinomas are still unclear. To date, one of the best-characterized genetic alterations leading to the development of poorly differentiated thyroid tumors is the loss of the p53 tumor suppressor gene. In addition, the existence of a complex network among p53 family members (p63 and p73) and their interactions with other factors that promote thyroid cancer progression has been well documented. In this review, we provide an update on the current knowledge of the role of p53 family proteins in thyroid cancer and their possible use as a therapeutic target for the treatment of the most aggressive variants of this disease.

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Section: The P53 Protein Familysupporting

confidence: 92%

New Insights in Thyroid Cancer and p53 Family Proteins

Manzella

Stella

Pennisi

et al. 2017

IJMS

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“…Cells were lysed and processed as previously described [49]. The following antibodies were used for Immunoprecipation: anti-DDR1 (monoclonal antibody MAB2396, R&D System) and anti-HA.11 (monoclonal antibody 16B12, Covance).…”

Section: Methodsmentioning

confidence: 99%

Discoidin domain receptor 1 modulates insulin receptor signaling and biological responses in breast cancer cells

et al. 2017

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The fetal isoform A of the insulin receptor (IR-A) is frequently overexpressed in a variety of malignancies including breast cancer. IR overexpression has a recognized role in cancer progression and resistance to anticancer therapies. In particular, IR-A has a peculiar mitogenic potential and is activated not only by insulin but also by IGF-2. Previously, we identified discoidin domain receptor 1 (DDR1) as a new IR-A interacting protein. DDR1, a non-integrin collagen tyrosine kinase receptor, is overexpressed in several malignancies and plays a role in cancer progression and metastasis.We now evaluated whether DDR1 is able to exert a role in breast cancer biology by functionally cross-talking with IR. In MCF-7 human breast cancer cells, IR and DDR1 co-immunoprecipitated and co-localized after insulin or IGF-2 stimulation. In a panel of breast cancer cells, DDR1 knockdown by specific siRNAs markedly inhibited IR downstream signaling as well as proliferation, migration and colony formation in response to insulin and IGF-2. These effects were accompanied by reduction of IR protein and mRNA expression, which involved both transcriptional and post-transcriptional effects. DDR1 overexpression elicited opposite effects. Bioinformatics analysis of public domain databases showed that IR and DDR1 co-expression significantly correlates with several clinically relevant histopathological and molecular features of human breast carcinomas.These findings demonstrate that, in human breast cancer cells, DDR1 regulates IR expression and ligand dependent biological actions. This novel functional crosstalk is likely clinically relevant and may become a new molecular target in breast cancer.

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“…For the analysis of crude lysates, Western blot analyses were performed as described previously (26). Briefly, cell lysates were incubated at 4 C under constant rotation for 1 h. After protein normalization, determined by the Bradford assay, proteins were eluted and subjected to SDS-PAGE.…”

Section: Immunoprecipitation and Western Blot Analysismentioning

confidence: 99%

Palmitate Affects Insulin Receptor Phosphorylation and Intracellular Insulin Signal in a Pancreatic α-Cell Line

et al. 2010

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This study investigated in a pancreatic alpha-cell line the effects of chronic exposure to palmitate on the insulin and IGF-I receptor (IGF-IR) and intracellular insulin pathways. alpha-TC1-6 cells were cultured in the presence or absence of palmitate (0.5 mmol/liter) up to 48 h. Glucagon secretion, insulin and IGF-IR autophosphorylation, and insulin receptor substrate (IRS)-1, IRS-2, phosphatidylinositol kinase (PI3K) (p85 alpha), and serine-threonine protein kinase (Akt) phosphorylated (active) forms were measured. Erk 44/42 and p38 phosphorylation (P) (MAPK pathway markers) were also measured. Because MAPK can regulate Pax6, a transcription factor that controls glucagon expression, paired box gene 6 (Pax6) and glucagon gene and protein expression were also measured. Basal glucagon secretion was increased and the inhibitory effect of acute insulin exposure reduced in alpha-TC1 cells cultured with palmitate. Insulin-stimulated insulin receptor phosphorylation was greatly reduced by exposure to palmitate. Similar results were observed with IRS-1-P, PI3K (p85 alpha), and Akt-P. In contrast, with IGF-IR and IRS-2-P, the basal levels (i.e. in the absence of insulin stimulation) were higher in cells cultured with palmitate. Similar data were obtained with Erk 44/42-P and p-38-P. Pax6 and glucagon gene and protein expression were higher in cells cultured with palmitate. In these cells cultured, specifics MAPKs inhibitors were able to reduce both Pax6 and glucagon gene and protein expression. These results indicate that alpha-cells exposed to palmitate show insulin resistance of the IRS-1/PI3K/Akt pathway that likely controls glucagon secretion. In contrast, the IRS-2/MAPKs pathway is stimulated, through an activation of the IGF-IR, leading to increased Pax6 and glucagon expression. Our data support the hypothesis that the chronic elevation of fatty acids contribute to alpha-cell dysregulation frequently observed in type 2 diabetes.

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TAp73α Increases p53 Tumor Suppressor Activity in Thyroid Cancer Cells via the Inhibition of Mdm2-Mediated Degradation

Cited by 23 publications

References 64 publications

New Insights in Thyroid Cancer and p53 Family Proteins

New Insights in Thyroid Cancer and p53 Family Proteins

Discoidin domain receptor 1 modulates insulin receptor signaling and biological responses in breast cancer cells

Palmitate Affects Insulin Receptor Phosphorylation and Intracellular Insulin Signal in a Pancreatic α-Cell Line

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