Novel functions of SMG-1 in carcinogenesis
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
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.
Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2013. , 47 p.
Biochemistry and Molecular Biology
Research subject Molecular Genetics
IdentifiersURN: urn:nbn:se:su:diva-96037ISBN: 978-91-7447-806-8OAI: oai:DiVA.org:su-96037DiVA: diva2:662819
2013-12-06, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 13:00 (English)
Gudkov, Andrei, Professor
At the time of the doctoral defence the following paper was unpublished and had a status as follows: Paper 3: Manuscript.2013-11-142013-11-082013-11-12Bibliographically approved
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