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Identifier

000381555

Title

Study of the role and regulation of Tpl2/COT(MAP3K8)in lung carcinogenesis : a proto-oncogene with a tumor suppressive function

Alternative Title

Μελέτη του ρόλου και της ρύθμισης της TPL2/COT(MAP3K8)στην καρκινογένεση του πνεύμονα:

Author

Γκιρτζιμανάκη, Π Αικατερίνη

Thesis advisor

Ηλιόπουλος, Αριστείδης

Reviewer

Παπαδάκη, Ελένη
Μαμαλάκη, Κ.

Abstract

Cancer can be perceived as a disease of communication between and within cells. The aberrations are pleiotropic, but mitogen‐activated protein kinase (MAPK) pathways feature prominently. Tpl2/COT is a serine‐threonine MAPK kinase kinase (MAP3K8) at the crossroad of various signal transduction pathways that control fundamental cellular processes such as growth, proliferation, differentiation, mi‐gration and apoptosis. Despite early studies identifying Tpl2 as a proto‐oncogene activated by C‐terminal truncation in mouse and rat, a detailed evaluation of its expression and function in human malignancy is missing and the physiological role of Tpl2/COT in carcinogenesis remains enigmatic. One of the three major human tissues where Tpl2 is expressed at highest levels is the lung. Lung cancer is the leading cause of cancer related death worldwide, re‐flecting the need for a better understanding of the mechanisms that underlie the development of pulmonary carcinomas. The Ph.D. thesis presented here focuses on the characterization of the role and of the mechanisms regulating the expres‐sion of Tpl2/COT1 in lung tumor cells during the onset of lung cancer development and through its progression. In this regard, we were able to reveal an unprecedented role for Tpl2/COT as sup‐pressor of lung carcinogenesis. This conclusion was based on a number of novel findings obtained through the extensive analysis of human tissue and of ex vivo and in vivo experimental models. We showed that COT expression is significantly reduced in human lung cancer compared to normal lung tissue providing the first demonstration that COT can be differentially expressed in a human malignancy. Importantly, the downregulation of COT is found to be of clinical relevance as it correlates with a more aggressive tumor phenotype and with poor prognosis in pa‐tients with lung cancer. Our data disclose 3 mechanisms responsible for COT downregulation in primary human lung tumors: (i) allelic imbalance at the COT locus; (ii) global DNA hypomethylation‐associated upregulation of miR‐370 which targets COT tran‐ 1 The term “Tpl2” is used for the mouse gene and protein product whereas the term “COT” refers to the human product. 10 scripts and (iii) activated Ras signaling affecting both COT transcription and protein stability. The operation of multiple genetic and epigenetic aberrations leading to loss of wild‐type COT in primary lung tumors underlines a previously unappreciat‐ed broader role for this pathway in lung carcinogenesis. This is corroborated by our experimental data showing that ablation of the Tpl2 gene in mice dramatically ac‐celerates the onset and multiplicity of urethane‐induced lung tumorigenesis. Additionally, we provide mechanistic evidence to suggest that Tpl2/COT antago‐nizes oncogene‐induced cell transformation and survival through a pathway involv‐ing the tumor suppressor p53 downstream of JNK. In particular, our studies define Tpl2/COT as a novel physiological antagonist of oncogenic Ras, thus also expanding our understanding of signaling and function of this major human oncogene. An im‐portant functional interaction between Tpl2/COT, JNK and p53 which controls apoptosis is revealed, providing a telling example of how tumor cells usurp alter‐native pathways that lower intrinsic barriers to malignant transformation.

Language

English

Subject

COT (cancer osaka thyroid)

JNK(c-jun n-terminal kinase)

MIR 370(micro-RNA 370)

Map3k8(mittogen activated protein 3 kinase 8)

NPM(nucleophosmin )

P53

RAS

Tpl2 (tumor progression locus 2)

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