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  • 1.
    Gubanova, Evgenia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Novel functions of SMG-1 in carcinogenesis2013Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Damage to DNA can cause mutations leading to cancer, and the DNA damage response (DDR), leading to transient cell-cycle arrest, DNA repair, senescence and apoptosis, plays a role in preventing tumor formation. At the same time, agents that damage DNA are used as anticancer therapy. The DDR has been extensively studied since the mid-nineties, when the genes of the major checkpoint kinases involved were cloned. Since then, quite a detailed model of the DDR has been worked out. According to the current model, the proximal stress-responsive kinases that are essential for the whole signaling cascade to function properly are ATM and ATR belonging to the family of phosphatidyl-inositol 3-kinase-related kinases (PIKKs). SMG-1 is the latest addition to this family, and accumulating evidence is pointing to its role in genome surveillance.

    In Paper I, we showed that SMG-1 regulates the G1/S checkpoint in response to ionizing radiation (IR) by two mechanisms. In addition to regulating the p53/p21 pathway by phosphorylating p53 and thus regulating its stability and activity, we have demonstrated a novel role for SMG-1 in regulating cell cycle progression and tumor growth via the p53-independent pathway. We identified Cdc25A as a new SMG-1 substrate and found that SMG-1 suppresses CDK2 activity in response to DNA damage, as well as in unperturbed cells.

    Head and neck squamous cell carcinoma (HNSCC) is divided into human papillomavirus (HPV)-positive and HPV-negative subgroups, of which HPV-positive cancers are sensitive to IR treatment and show a more favorable prognosis compared to HPV-negative HNSCCs.  In Paper II, for the first time, we have shown a link between defects in SMG-1 expression and cancer. We demonstrated that HPV-positive HNSCC cancer cell lines and tumors express SMG-1 at lower levels than HPV-negative HNSCCs due to promoter hypermethylation. We concluded that diminished SMG-1 levels may contribute to the enhanced response to radiation therapy exhibited by HPV-positive HNSCCs.  

    Senescence and epithelial-mesenchymal transition (EMT) are both tightly linked to carcinogenesis. Oncogene-induced senescence (OIS) functions as a barrier against tumor progression, while EMT promotes tumor progression and metastasis. In Paper III, we identified previously unknown roles of SMG-1 in these two cellular processes. SMG-1 deficient cells failed to initiate the OIS program induced by activation of Ras. Downregulation of SMG-1 also induced morphologic and molecular changes consistent with EMT. We propose that, by regulating senescence and suppressing EMT, SMG-1 inhibits cancer progression. 

  • 2.
    Gubanova, Evgenia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Brown, Brandee
    Ivanov, Sergei V.
    Helleday, Thomas
    Mills, Gordon B.
    Yarbrough, Wendell G.
    Issaeva, Natalia
    Downregulation of SMG-1 in HPV-Positive Head and Neck Squamous Cell Carcinoma Due to Promoter Hypermethylation Correlates with Improved Survival2012Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, nr 5, s. 1257-1267Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Human papillomavirus (HPV) is linked with a subset of head and neck squamous cell carcinomas (HNSCC). HPV-positive HNSCCs show a better prognosis than HPV-negative HNSCCs, which may be explained by sensitivity of the HPV-positive HNSCCs to ionizing radiation (IR). Although the molecular mechanism behind sensitivity to IR in HPV-positive HNSCCs is unresolved, DNA damage response (DDR) might be a significant determinant of IR sensitivity. An important player in the DDR, SMG-1 (suppressor with morphogenetic effect on genitalia), is a potential tumor suppressor and may therefore be deregulated in cancer. No studies have yet been conducted linking defects in SMG-1 expression with cancer. We investigated whether deregulation of SMG-1 could be responsible for defects in the DDR in oropharyngeal HNSCC. Experimental Design: Expression and promoter methylation status of SMG-1 were investigated in HNSCCs. To identify a functional link between HPV infection and SMG-1, we transfected the HPV-negative cells with an E6/E7 expression construct. SMG-1 short hairpin RNAs were expressed in HPV-negative cells to estimate survival upon IR. Results: Forced E6/E7 expression in HPV-negative cells resulted in SMG-1 promoter hypermethylation and decreased SMG-1 expression. Due to promoter hypermethylation, HPV-positive HNSCC cells and tumors express SMG-1 at lower levels than HPV-negative SCCs. Depletion of SMG-1 in HPV-negative HNSCC cells resulted in increased radiation sensitivity, whereas SMG-1 overexpression protected HPV-positive tumor cells from irradiation. Conclusions: Levels of SMG-1 expression negatively correlated with HPV status in cancer cell lines and tumors. Diminished SMG-1 expression may contribute to the enhanced response to therapy exhibited by HPV-positive HNSCCs. 

  • 3.
    Gubanova, Evgenia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Issaeva, Natalia
    Gokturk, Camilla
    Djureinovic, Tatjana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Helleday, Thomas
    SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways2013Inngår i: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 12, nr 24, s. 3770-3780Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The DNA damage response is coordinated by phosphatidylinositol 3-kinase-related kinases, ATM, ATR, and DNA-PK. SMG-1 is the least studied stress-responsive member of this family. Here, we show that SMG-1 regulates the G 1/S checkpoint through both a p53-dependent, and a p53-independent pathway. We identify Cdc25A as a new SMG-1 substrate, and show that cells depleted of SMG-1 exhibit prolonged Cdc25A stability, failing to inactivate CDK2 in response to radiation. Given an increased tumor growth following depletion of SMG-1, our data demonstrate a novel role for SMG-1 in regulating Cdc25A and suppressing oncogenic CDK2 driven proliferation, confirming SMG-1 as a tumor suppressor.

  • 4.
    Issaeva, Natalia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Thomas, Huw D.
    Djurenovic, Tatjana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Jaspers, Janneke E.
    Stoimenov, Ivaylo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Kyle, Suzanne
    Pedley, Nicholas
    Gottipati, Ponnari
    Zur, Rafal
    Sleeth, Kate
    Chatzakos, Vicky
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Mulligan, Evan A.
    Lundin, Cecilia
    Gubanova, Evgenia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Kersbergen, Ariena
    Harris, Adrian L.
    Sharma, Ricky A.
    Rottenberg, Sven
    Curtin, Nicola J.
    Helleday, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    6-Thioguanine Selectively Kills BRCA2-Defective Tumors and Overcomes PARP Inhibitor Resistance2010Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, nr 15, s. 6268-6276Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors were tested for these tumors in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-thioguanine (6TG), which induces DNA double-strand breaks (DSB) that are repaired by HR. Furthermore, we show that 6TG is as efficient as a PARP inhibitor in selectively killing BRCA2-defective tumors in a xenograft model. Spontaneous BRCA1-defective mammary tumors gain resistance to PARP inhibitors through increased P-glycoprotein expression. Here, we show that 6TG efficiently kills such BRCA1-defective PARP inhibitor-resistant tumors. We also show that 6TG could kill cells and tumors that have gained resistance to PARP inhibitors or cisplatin through genetic reversion of the BRCA2 gene. Although HR is reactivated in PARP inhibitor-resistant BRCA2-defective cells, it is not fully restored for the repair of 6TG-induced lesions. This is likely to be due to several recombinogenic lesions being formed after 6TG. We show that BRCA2 is also required for survival from mismatch repair-independent lesions formed by 6TG, which do not include DSBs. This suggests that HR is involved in the repair of 6TG-induced DSBs as well as mismatch repair-independent 6TG-induced DNA lesion. Altogether, our data show that 6TG efficiently kills BRCA2-defective tumors and suggest that 6TG may be effective in the treatment of advanced tumors that have developed resistance to PARP inhibitors or platinum-based chemotherapy. Cancer Res; 70(15); 6268-76. (C) 2010 AACR.

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