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Novel functions of SMG-1 in carcinogenesis
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
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. 

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2013. , 47 p.
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:su:diva-96037ISBN: 978-91-7447-806-8 (print)OAI: oai:DiVA.org:su-96037DiVA: diva2:662819
Public defence
2013-12-06, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defence the following paper was unpublished and had a status as follows: Paper 3: Manuscript.

Available from: 2013-11-14 Created: 2013-11-08 Last updated: 2013-11-12Bibliographically approved
List of papers
1. SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways
Open this publication in new window or tab >>SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways
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2013 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 12, no 24, 3770-3780 p.Article in journal (Refereed) Published
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.

Keyword
Cdc25A, CDK2, cell cycle, G1/S checkpoint, p53, SMG-1, tumorigenesis, tumor suppressor
National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:su:diva-96163 (URN)10.4161/cc.26660 (DOI)000330524800016 ()
Available from: 2013-11-12 Created: 2013-11-12 Last updated: 2017-12-06Bibliographically approved
2. Downregulation of SMG-1 in HPV-Positive Head and Neck Squamous Cell Carcinoma Due to Promoter Hypermethylation Correlates with Improved Survival
Open this publication in new window or tab >>Downregulation of SMG-1 in HPV-Positive Head and Neck Squamous Cell Carcinoma Due to Promoter Hypermethylation Correlates with Improved Survival
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2012 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, no 5, 1257-1267 p.Article in journal (Refereed) Published
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. 

National Category
Microbiology Cancer and Oncology
Identifiers
urn:nbn:se:su:diva-76991 (URN)10.1158/1078-0432.CCR-11-2058 (DOI)000301040700010 ()
Note
7Available from: 2012-06-01 Created: 2012-05-28 Last updated: 2017-12-07Bibliographically approved
3. SMG-1 regulates senescence and suppresses epithelial-mesenchymal transition
Open this publication in new window or tab >>SMG-1 regulates senescence and suppresses epithelial-mesenchymal transition
(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:su:diva-96165 (URN)
Available from: 2013-11-12 Created: 2013-11-12 Last updated: 2013-11-12

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