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مجال التميز |
تميز دراسي وبحثي |
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البحوث المنشورة |
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البحث (1): |
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عنوان البحث: |
The Role of the HIF-1α Transcription Factor in Increased Cell Division at Physiological Oxygen Tensions |
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رابط إلى البحث: |
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تاريخ النشر: |
16 May 2014 |
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موجز عن البحث: |
HIF-1 is a transcription factor that mediates the cellular responses to low oxygen environments, mainly as a result of having an oxygen-labile subunit, HIF-1a. HIF-1a has been carefully studied in the context of severe hypoxic stresses (,1% O2), but itis also known to be present at oxygen tensions commonly found in normal tissues in vivo (,1–13% O2), albeit at much lower levels. Its role under these physiological conditions is not fully understood. Here, we show that a transcriptionally active HIF-1a was up-regulated at 5% O2, both in normal and cancer cells, but only some of its target genes were elevated as a result. HIF-1a induction was in part dependent on the activation of the ERK1/2 MAPK signalling pathway, which we have previously shown is active at 5% O2. We also found that HIF-1a does not contribute to the protection against DNA damage that can be observed in low oxygen environments, and that there are certain DNA damaging agents, such as doxorubicin and actinomycin D, that prevent HIF-1a induction independently of p53. Moreover, absence of HIF-1a significantly reduced the growth advantage of cells cultured at 5% O2. In view of these data, we conclude that HIF-1a can be induced and activated at physiological oxygen tensions in a MAPK-dependent manner and that, although this does not lead to pro-survival responses to stress, it determines the increased cell proliferation rates that are common under these conditions. |
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البحث (2): |
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عنوان البحث: |
Characterization of novel markers of senescence and their prognostic potential in cancer. |
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رابط إلى البحث: |
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تاريخ النشر: |
20 November 2014 |
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موجز عن البحث: |
Cellular senescence is a terminal differentiation state that has been proposed to have a role in both tumour suppression and ageing. This view is supported by the fact that accumulation of senescent cells can be observed in response to oncogenic stress as well as a result of normal organismal ageing. Thus, identifying senescent cells in in vivo and in vitro has an important diagnostic and therapeutic potential. The molecular pathways involved in triggering and/or maintaining the senescent phenotype are not fully understood. As a consequence, the markers currently utilized to detect senescent cells are limited and lack specificity. In order to address this issue, we screened for plasma membrane-associated proteins that are preferentially expressed in senescent cells. We identified 107 proteins that could be potential markers of senescence and validated 10 of them (DEP1, NTAL, EBP50, STX4, VAMP3, ARMX3, B2MG, LANCL1, VPS26A and PLD3). We demonstrated that acombination of these proteins can be used to specifically recognize senescent cells in culture and in tissue samples and we developed a straightforward fluorescence-activated cell sortingbased detection approach using two of them (DEP1 and B2MG). Of note, we found that expression of several of these markers correlated with increased survival in different tumours, especially in breast cancer. Thus, our results could facilitate the study of senescence, define potential new effectors and modulators of this cellular mechanism and provide potential diagnostic and prognostic tools to be used clinically. |
