Hypoxia induces class III beta-tubulin gene expression by HIF-1α binding to its 3' flanking region

Raspaglio, Giuseppina; Filippetti, Flavia; Prislei, Silvia; Penci, Roberta; Maria, Ilaria De; Cicchillitti, Lucia; Mozzetti, Simona; Scambia, Giovanni; Ferlini, Cristiano

doi:10.1016/j.gene.2007.11.015

Cited by 108 publications

(101 citation statements)

References 27 publications

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“…This function is enhanced in drug-resistant cells, thereby providing them the ability to survive the solid tumor microenvironment of the most aggressive diseases. This finding complements our recent discovery that TUBB3 is a factor activated by hypoxia and under the transcriptional control of HIF-1a (35).…”

Section: Molecular Cancer Therapeutics 2077supporting

confidence: 88%

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

Cicchillitti¹,

Penci²,

Michele

et al. 2008

Molecular Cancer Therapeutics

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Class III B-tubulin (TUBB3) has been discovered as a marker of drug resistance in human cancer. To get insights into the mechanisms by which this protein is involved in drug resistance, we analyzed TUBB3 in a panel of drug-sensitive and drug-resistant cell lines. We identified two main different isoforms of TUBB3 having a specific electrophoretic profile. We showed that the apparently higher molecular weight isoform is glycosylated and phosphorylated and it is localized in the cytoskeleton. The apparently lower molecular weight isoform is instead found exclusively in mitochondria. We observed that levels of phosphorylation and glycosylation of TUBB3 are associated with the resistant phenotype and compartmentalization into cytoskeleton. By two-dimensional nonreduced/reduced SDS-PAGE analysis, we also found that TUBB3 protein in vivo forms protein complexes through intermolecular disulfide bridges. Through TUBB3 immunoprecipitation, we isolated protein species able to interact with TUBB3. Following trypsin digestion, these proteins were characterized by mass spectrometry analysis. Functional analysis revealed that these proteins are involved in adaptation to oxidative stress and glucose deprivation, thereby suggesting that TUBB3 is a survival factor able to directly contribute to drug resistance. Moreover, glycosylation of TUBB3 could represent an attractive pathway whose inhibition could hamper cytoskeletal compartmentalization and TUBB3 function.

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Section: Molecular Cancer Therapeutics 2077supporting

confidence: 88%

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

Cicchillitti¹,

Penci²,

Michele

et al. 2008

Molecular Cancer Therapeutics

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“…To our knowledge this is the first article addressing the role of TUBB3 in colorectal cancer. Recent findings support the notion that the TUBB3 pathway is an adaptive response to exposure to microenvironmental stressors, such as hypoxia and poor nutrient supply (5,6). For this reason TUBB3 is a biomarker of biologic aggressiveness and the tendency toward metastasis (7).…”

Section: Discussionsupporting

confidence: 53%

“…Although originally identified as a mechanism of drug resistance to taxanes (4), recent studies have shown that TUBB3 is involved in an adaptive response to low oxygen levels and poor nutrient supply in a growing number of solid tumors (5,6). This explains the involvement of TUBB3 in drug resistance independent of whether the disease is treated with a regimen that includes a microtubule targeting agent or not (7).…”

Section: Introductionmentioning

confidence: 99%

Gender Influences the Class III and V β-Tubulin Ability to Predict Poor Outcome in Colorectal Cancer

Mariani

Zannoni

Sioletic

et al. 2012

Clinical Cancer Research

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Purpose: Colorectal cancer is one of the deadliest diseases in Western countries. To predict the outcome of therapy, we assessed the role of class III (TUBB3) and class V b-tubulin (TUBB6) as predictive biomarkers.Experimental Design: Using immunohistochemistry and nanofluidics, the expression of TUBB3 and TUBB6 was assessed in two cohorts of 180 and 134 patients, respectively. The CYP17A1 RS743572 was genotyped to identify GG carriers with enhanced androgen levels. TUBB3 and TUBB6 were investigated in 22 colorectal cancer cell lines in basal conditions and after serum starvation, the latter serving as activator of this prosurvival pathway. To ascertain the role of androgen receptor (AR) in such regulation, we silenced AR and checked TUBB3 and TUBB6 expression and sensitivity to chemotherapy.Results: There was a link between poor survival, the expression of TUBB3/TUBB6, and AR only in females. Conversely, only in males carriers of the GG phenotype exhibited the worst outcome. Importantly, male cell lines were resistant to serum starvation and exhibited higher levels of TUBB6, thereby suggesting that the pathway is activated by androgens. In female cells this phenomenon was absent. In both genders, AR was the main driver of TUBB3/TUBB6 expression, as constitutive silencing of AR was associated with downregulation of TUBB3/TUBB6 expression and increased sensitivity to oxaliplatin and SN-38.Conclusions: The involvement of androgens in the TUBB3 pathway opens the way for clinical trials to assess the efficacy of antiandrogens for increasing the efficacy of chemotherapy in male colorectal cancer patients.

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“…This is evident in the erythropoietin and the class III beta-tubulin genes, where it has been shown that hypoxia-induced expression is dependent upon the tissuespecific methylation status of a HRE in the 3'-UTR. [17][18][19] As global changes in DNA methylation can occur under chronic hypoxic conditions, it is possible that this may impact on the methylation status of HRE sites, 1,20 and thus shape the HIF-dependent transcriptional profile according to the intensity and duration of the hypoxic insult. Gene specific DNA hypomethylation may reveal previously inaccessible HIF binding sites, thus exposing new active regions for HIF or other hypoxia-responsive transcription factors.…”

Section: Methylation In Hypoxiamentioning

confidence: 99%

Epigenetics: The epicenter of the hypoxic response

Watson¹,

Watson²,

McCann³

et al. 2010

Epigenetics

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Hypoxia induces class III beta-tubulin gene expression by HIF-1α binding to its 3' flanking region

Cited by 108 publications

References 27 publications

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

Gender Influences the Class III and V β-Tubulin Ability to Predict Poor Outcome in Colorectal Cancer

Epigenetics: The epicenter of the hypoxic response

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