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BBA - Reviews on Cancer (v.1755, #2)
Cellular UV damage responses—Functions of tumor suppressor p53 by Leena Latonen; Marikki Laiho (pp. 71-89).
DNA damage, provoked by ultraviolet (UV) radiation, evokes a cellular damage response composed of activation of stress signaling and DNA checkpoint functions. These are translated to responses of replicative arrest, damage repair, and apoptosis aimed at cellular recovery from the damage. p53 tumor suppressor is a central stress response protein, activated by multiple endogenous and environmental insults, including UV radiation. The significance of p53 in the DNA damage responses has frequently been reviewed in the context of ionizing radiation or other double strand break (DSB)-inducing agents. Despite partly similar patterns, the molecular events following UV radiation are, however, distinct from the responses induced by DSBs and are profoundly coupled with transcriptional stress. These are illustrated, e.g., by the UV damage-specific translocations of Mdm2, promyelocytic leukemia protein, and nucleophosmin and their interactions with p53. In this review, we discuss UV damage-provoked cellular responses and the functions of p53 in damage recovery and cell death.
Keywords: Abbreviations; 6-4PP; 6-4 photoproduct; ATM; ataxia telangiectasia mutated; ATR; ataxia telangiectasia-related; CPD; cyclobytane-type pyrimidine dimer; DSB; double strand break; GGR; global genomic repair; HDAC; histone deacetylase; HAT; histone acetyl transferase; NB; nuclear bodies; NER; nucleotide excision repair; NPM; nucleophosmin; PML; promyelocytic leukemia; RNAP; RNA polymerase; ROS; reactive oxygen species; TAD; transactivation domain; TCR; transcription-coupled repair; UV; ultraviolet; Wt; wild type; XP; Xeroderma pigmentosump53 tumor suppressor; UV radiation; DNA damage; Nucleotide excision repair; Cell cycle arrest; Apoptosis
Ultraviolet radiation-induced apoptosis in keratinocytes: On the role of cytosolic factors by Zerihun Assefa; An Van Laethem; Marjan Garmyn; Patrizia Agostinis (pp. 90-106).
Epidemiological and experimental evidences have established solar ultraviolet (UV) radiation as the leading cause of skin cancers. Specifically, the frequency of non-melanoma skin cancer, one of the malignancies with the most rapidly increasing incidence, is directly related to the total exposure to solar UV light. As part of a general effort to elucidate the components of cellular signal transduction pathways, the mechanisms of cellular responses to UV radiation have received considerable attention over the last few years. These efforts were driven mainly by the conviction that understanding how normal cells respond to extracellular stimuli such as exposure to UV radiation will undoubtedly help in deciphering what goes wrong in a variety of clinical disorders including skin cancers and will assist in the development of novel therapeutic strategies. Studies over the last decade have established that UV radiation induces a bewildering array of signal transduction pathways, some of which could lead to apoptotic cell death. UV-induced cell death by apoptosis is considered to be a natural protective mechanism that removes damaged keratinocytes and circumvents the risk of malignant transformation. In this review, we summarize some of the most important findings regarding the response and role of mitogen-activated protein kinases in UVA and UVB radiation-induced signaling to apoptosis in keratinocytes. We will also briefly discuss what is known about the role of the BCL-2 family of proteins, the emerging role of lysosomal proteases and other important cytosolic signaling proteins in UV-induced apoptosis.
Keywords: Ultraviolet radiation; Apoptosis; MAPK; BCL-2; Keratinocytes; Photocarcinogenesis
Negative and positive regulation of HIF-1: A complex network by Julia I. Bárdos; Margaret Ashcroft (pp. 107-120).
Hypoxia inducible factor-1 (HIF-1) is as a key transcriptional mediator of the hypoxic response in eukaryotic cells, regulating the expression of a myriad of genes involved in oxygen transport, glucose uptake and glycolysis and angiogenesis. Deregulation of HIF-1 activity occurs in many human cancers, usually at the level of the HIF-1α subunit. HIF-1 is regulated by a variety of mechanisms including transcription, translation post-translational modification, protein-protein interaction and degradation. Our understanding of the key signalling pathways that regulate HIF-1 has significantly progressed in recent years and has highlighted the potential for targeting the HIF-1 pathway as a basis for the development of new cancer therapies.
Keywords: Hypoxia inducible factor-1; HIF-1α; HIF-2α; Hypoxia; Growth factors; Tumour suppressor protein; Oncogenic signalling
In silico analysis of angiogenesis associated gene expression identifies angiogenic stage related profiles by Judy R. van Beijnum; Arjan W. Griffioen (pp. 121-134).
In vitro models have been extensively used to map gene expression in ECs but few studies have used cells from in vivo sources directly. Here, we compare different gene expression surveys on both cultured and fresh tissue derived ECs, and it emerges that gene expression profiles can be paralleled with the angiogenic stage of the cells. ECs stimulated with different growth factors in monolayer cultures exhibit gene expression profiles indicative of an active proliferative state, whereas gene expression in tube forming cells in vitro involves genes implicated in cell adhesion processes. Genes overexpressed in tumor ECs are biased towards extracellular matrix remodeling, a late event in angiogenesis. The elucidation of gene expression profiles under these different conditions will contribute to a better understanding of the molecular mechanisms during angiogenesis in both pathological and physiological circumstances and will have implications for the development of angiogenesis interfering treatment strategies.
Keywords: Angiogenesis; Gene expression profiling; Tumor endothelial marker; Extracellular matrix; Angiogenesis assay; EC heterogeneity
Cyclooxygenase-2 and prostaglandin signaling in cholangiocarcinoma by Tong Wu (pp. 135-150).
Cholangiocarcinoma is a highly malignant epithelial neoplasm arising within the biliary tract and its incidence and mortality is rising. Early diagnosis is difficult and there is presently no effective treatment. Significant progress has been made over the past several years in defining the link between COX-2 and cholangiocarcinogenesis. Selective COX-2 inhibitors have been shown to inhibit cholangiocarcinoma cell growth in vitro and in animal models. However, recently, concerns have been raised about the cardiovascular side effect associated with some COX-2 inhibitors utilized at relatively high dose for antitumor chemoprevention, despite that these inhibitors have a proven safety profile when given as monotherapy to arthritis patients. Therefore, there is an urgent and practical need to develop novel chemopreventive strategy that simultaneously targets COX-2 signaling and other related key molecules in cholangiocarcinogenesis, such as EGFR or utilization of agents inhibiting COX-2 signaling in conjunction with other standard chemotherapy or radiation therapy; these approaches are expected to provide synergistic anti-tumor effect with lesser side effect. In this context, the recently delineated interplay between COX-2-derived PG signaling and other growth-regulatory pathways, such as EGFR, ErbB2, IL-6/GP130, HGF/Met, TGF-β/Smad, and iNOS is expected to provide important therapeutic implications. This review will summarize the recent advances in understanding the mechanisms for COX-2-derived PG signaling in cholangiocarcinogenesis and focus on the newly unveiled interactions between PG cascade and other key signaling pathways that coordinately regulate cholangiocarcinoma growth. Knowledge on these aspects will help develop more effective therapeutic strategy targeting COX-2 and related key signaling molecules.
Keywords: Abbreviations; AA; arachidonic acid; Akt; also known as serine/threonine protein kinase B (PKB); BEC; biliary epithelial cell; COX-2; cyclooxygenase-2; cPLA; 2; cytosolic phospholipase A; 2; EGFR; epidermal growth factor receptor; HGF; hepatocyte growth factor; IL-6; interleukin-6; iNOS; inducible nitric oxide synthase; MAPK; mitogen activated protein kinase; NSAID; nonsteroidal anti-inflammatory drug; PLA; 2; phospholipase A; 2; PG; prostaglandin; PPAR-γ; peroxisome proliferator activated receptor-γ; PSC; primary sclerosing cholangitis; TGF-β; transforming growth factor-βCyclooxygenase-2; Prostaglandin E; 2; EP; 1; receptor; Cholangiocarcinoma