Mechanisms Behind the Oncogene-induced Senescence (OIS) - Oncogene-induced Apoptosis (OIA) Decision in Cells Expressing P95HER2 PDF Download
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Author: Cristina Bernadó Morales
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Author: Cristina Bernadó Morales
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Author: Samantha Garnett
Publisher:
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Category :
Languages : en
Pages :
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"Cancer is caused by the accumulation of genetic mutations that promote the abnormal growth of cells. Oncogene Induced Senescence (OIS), a tumour suppressive mechanism, provides a robust barrier to proliferation promoted by commonly mutated oncogenes, such as Raf or Ras, and the bypass of this barrier is a critical event on the path to malignancy. The mechanisms involved in OIS bypass are not yet fully understood. Many questions remain such as whether the timing of genetic mutations is relevant, whether additional mutations can permit escape from OIS, what cellular processes are required to establish OIS, and how senescent tumour cells can contribute to the tissue microenvironment.Using a Flp-activated Braf allele paired with a Cre-conditionally null p53 allele, p53 was ablated at six independent timepoints following the initiation of BrafV600E lung adenomas in the mouse lung, allowing for temporal dissection of tumour progression and OIS. Using this dual-recombinase system, it was determined that p53 loss after OIS is established is not sufficient to permit malignant adenocarcinoma (LUAD) development. BrafV600E adenomas are stably restrained from malignancy by OIS by approximately 24 weeks after BrafV600E expression, and several senescence and SASP markers can be detected in those adenomas. Interestingly, the length of time until OIS establishment could be modulated by the initiating viral titres of adenoviral-Flp. Lower initiating adenoviral titre produced lower tumour density in the lung that was correlated with smaller, more proliferative tumours. Lower-density tumour environments also permitted bypass of OIS and LUAD development at 24-32 weeks, suggesting that higher proliferation is due to delay in OIS. Finally, a search for new modulators of OIS was conducted. Using an shRNA-based lentiviral genetic screen, IAPP or amylin, a small metabolic regulator, was shown to be required for BRAF induced senescence. Both loss of IAPP, and its receptor RAMP3, permitted bypass of oncogene induced senescence. IAPP is a glycolysis inhibitor and this thesis links IAPP-regulated metabolic programming to OIS and the functions of the chromatin remodellers known as Jumonji Histone Demethylases. Together this work contributes new insight into the mechanisms underlying OIS and how these might be bypassed in the case of cancer development"--
Author: M.A. Hayat
Publisher: Springer Science & Business Media
ISBN: 9400777264
Category : Science
Languages : en
Pages : 336
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Book Description
In this second volume in the series exploring Tumor Dormancy, Quiescence, and Cellular Senescence, discussion is focused on the role of tumor dormancy in diseases such as breast cancer, melanoma, prostate cancer, liver cancer and lung cancer. M. A. Hayat, the series editor, writes in the preface that little is known of factors regulating the transition of residual cancer into a dormant state or the subsequent reinitiation of growth. A majority of us, he says, have in situ tumors that may remain dormant or may progress into a lethal form of cancer; the former are prevented from recruiting their own blood supply. Section I covers Molecular Mechanisms, with chapters on the role of NAE inhibitor MLN4924; oncogene-induced senescence; the role played by mitogen-activated protein kinase in the induction of cellular senescence; mechanisms of premature cell senescence and other topics. Section II examines Tumor and Cancer, discussing defects in chromatin structure and diseases; the role of fibrosis in tumor progression and the dormant to proliferative switch; the function of ING proteins in cancer and senescence and more. The final section is devoted to Stem Cells and Cancer Stem Cells, featuring chapters showing that senescent-derived pluripotent stem cells are able to redifferentiate into fully rejuvenated cells; that the transcription factor Gata2 regulates quiescence in haematopoietic stem and progenitor cells; and discussing dormancy and recurrence of cancer stem cells in bone. The contributors point out that the quiescent state regulates hematopoietic stem cells and muscle stem cells, and detail the role of kinase in the mediation of reversible quiescent state in a subset of ovarian, pancreatic, and colon cancers. Molecular mechanisms underlying stress-induced cellular senescence and accumulation of reactive oxygen species and induction of premature senescence are also presented. Discussion includes the important role of microRNAs in oxidative stress-induced apoptosis and senescence and the effect of microRNA as a modulator of cell proliferation in lung cancer. The book includes an explanation of the suppression of cellular senescence in glioblastoma brain tumor. Taking a broad and varied perspective, this volume was written by 70 contributors representing 11 countries.
