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BBA - Reviews on Cancer (v.1795, #1)
Protein phosphatase 2A regulatory subunits and cancer
by Pieter J.A. Eichhorn; Menno P. Creyghton; René Bernards (pp. 1-15).
The serine/threonine protein phosphatase (PP2A) is a trimeric holoenzyme that plays an integral role in the regulation of a number of major signaling pathways whose deregulation can contribute to cancer. The specificity and activity of PP2A are highly regulated through the interaction of a family of regulatory B subunits with the substrates. Accumulating evidence indicates that PP2A acts as a tumor suppressor. In this review we summarize the known effects of specific PP2A holoenzymes and their roles in cancer relevant pathways. In particular we highlight PP2A function in the regulation of MAPK and Wnt signaling.
Keywords: Protein phosphatase 2A; Signal transduction; Cancer
Protein phosphatase 2A regulatory subunits and cancer
by Pieter J.A. Eichhorn; Menno P. Creyghton; René Bernards (pp. 1-15).
The serine/threonine protein phosphatase (PP2A) is a trimeric holoenzyme that plays an integral role in the regulation of a number of major signaling pathways whose deregulation can contribute to cancer. The specificity and activity of PP2A are highly regulated through the interaction of a family of regulatory B subunits with the substrates. Accumulating evidence indicates that PP2A acts as a tumor suppressor. In this review we summarize the known effects of specific PP2A holoenzymes and their roles in cancer relevant pathways. In particular we highlight PP2A function in the regulation of MAPK and Wnt signaling.
Keywords: Protein phosphatase 2A; Signal transduction; Cancer
Immunosuppressive networks in the tumour environment and their effect in dendritic cells
by Karim Bennaceur; Jessica Alice Chapman; Jean-louis Touraine; Jacques Portoukalian (pp. 16-24).
The failure of the immune system to provide protection against tumour cells is an important immunological problem. It is now evident that inadequate function of the host immune system is one of the main mechanisms by which tumours escape from immune control, as well as an important factor that limits the success of cancer immunotherapy. In recent years, it has become increasingly clear that defects in dendritic cells have a crucial role in non-responsiveness to tumours. This article focuses on the functional consequences and recently described mechanisms of the dendritic-cell defects in cancer.
Keywords: Tumour escape; Dendritic cell; Immune dysfunction; Tumour microenvironment
RETRACTED: Immunosuppressive networks in the tumour environment and their effect in dendritic cells
by Karim Bennaceur; Jessica Alice Chapman; Jean-louis Touraine; Jacques Portoukalian (pp. 16-24).
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the editor as the authors have plagiarized part of a paper that had already appeared in Nat. Rev. Immunol., 4 (2004) 941952, doi:10.1038/nri1498. One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and has not appeared in a publication elsewhere. Re-use of any data should be appropriately cited. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.
BAR the door: Cancer suppression by amphiphysin-like genes
by George C. Prendergast; Alexander J. Muller; Arivudanambi Ramalingam; Mee Young Chang (pp. 25-36).
The evolutionarily conserved amphiphysin-like genes Bin1 and Bin3 function in membrane and actin dynamics, cell polarity, and stress signaling. Recent genetic studies in mice discriminate non-essential roles in endocytic processes commonly ascribed to amphiphysins from essential roles in cancer suppression. Bin1 acts in default pathways of apoptosis and senescence that are triggered by the Myc and Raf oncogenes in primary cells, and Bin1 gene products display a ‘moonlighting function’ in the nucleus where a variety of other ‘endocytic’ proteins are also found. Together, genetic investigations in yeast, flies, and mice suggest that amphiphysin-like adapter proteins may suppress cancer by helping integrate cell polarity signals generated by actin and vesicle dynamics with central regulators of cell cycle arrest, apoptosis, and immune surveillance.
Keywords: Tumor suppressor; Modifier; Lung cancer; Vesicle trafficking; Indoleamine 2,3-dioxygenase; c-myc; Ras; Rho
BAR the door: Cancer suppression by amphiphysin-like genes
by George C. Prendergast; Alexander J. Muller; Arivudanambi Ramalingam; Mee Young Chang (pp. 25-36).
The evolutionarily conserved amphiphysin-like genes Bin1 and Bin3 function in membrane and actin dynamics, cell polarity, and stress signaling. Recent genetic studies in mice discriminate non-essential roles in endocytic processes commonly ascribed to amphiphysins from essential roles in cancer suppression. Bin1 acts in default pathways of apoptosis and senescence that are triggered by the Myc and Raf oncogenes in primary cells, and Bin1 gene products display a ‘moonlighting function’ in the nucleus where a variety of other ‘endocytic’ proteins are also found. Together, genetic investigations in yeast, flies, and mice suggest that amphiphysin-like adapter proteins may suppress cancer by helping integrate cell polarity signals generated by actin and vesicle dynamics with central regulators of cell cycle arrest, apoptosis, and immune surveillance.
Keywords: Tumor suppressor; Modifier; Lung cancer; Vesicle trafficking; Indoleamine 2,3-dioxygenase; c-myc; Ras; Rho
The multifaceted roles of the receptor tyrosine kinase ROS in development and cancer
by Jaime Acquaviva; Ricky Wong; Al Charest (pp. 37-52).
The proto-oncogene receptor tyrosine kinase ROS was originally discovered through the identification of oncogenic variants isolated from tumors. These discoveries spearheaded a body of work aimed at elucidating the function of this evolutionarily conserved receptor in development and cancer. Through genetic and biochemical approaches, progress in the characterization of ROS points to distinctive roles in the program of epithelial cell differentiation during the development of a variety of organs. Although substantial, these advances remain hampered by the absence of an identified ligand, making ROS one of the last two remaining orphan receptor tyrosine kinases. Recent studies on the oncogenic activation of ROS as a result of different chromosomal rearrangements found in brain and lung cancers have shed light on the molecular mechanisms underlying ROS transforming activities. ROS and its oncogenic variants therefore constitute clinically relevant targets for cancer therapeutic intervention. This review highlights the various roles that this receptor plays in multiple system networks in normalcy and disease and points to future directions towards the elucidation of ROS function in the context of ligand identification, signaling pathways and clinical applications.
Keywords: Cancer; c-ROS; Glioblastoma; Signal Transduction; Receptor; Kinase
The multifaceted roles of the receptor tyrosine kinase ROS in development and cancer
by Jaime Acquaviva; Ricky Wong; Al Charest (pp. 37-52).
The proto-oncogene receptor tyrosine kinase ROS was originally discovered through the identification of oncogenic variants isolated from tumors. These discoveries spearheaded a body of work aimed at elucidating the function of this evolutionarily conserved receptor in development and cancer. Through genetic and biochemical approaches, progress in the characterization of ROS points to distinctive roles in the program of epithelial cell differentiation during the development of a variety of organs. Although substantial, these advances remain hampered by the absence of an identified ligand, making ROS one of the last two remaining orphan receptor tyrosine kinases. Recent studies on the oncogenic activation of ROS as a result of different chromosomal rearrangements found in brain and lung cancers have shed light on the molecular mechanisms underlying ROS transforming activities. ROS and its oncogenic variants therefore constitute clinically relevant targets for cancer therapeutic intervention. This review highlights the various roles that this receptor plays in multiple system networks in normalcy and disease and points to future directions towards the elucidation of ROS function in the context of ligand identification, signaling pathways and clinical applications.
Keywords: Cancer; c-ROS; Glioblastoma; Signal Transduction; Receptor; Kinase
Epigenetic regulation of gap junctional intercellular communication: More than a way to keep cells quiet?
by Mathieu Vinken; Evelien De Rop; Elke Decrock; Elke De Vuyst; Luc Leybaert; Tamara Vanhaecke; Vera Rogiers (pp. 53-61).
The establishment of gap junctional intercellular communication is a prerequisite for appropriate control of tissue homeostasis. Gap junctions consist of connexin proteins, whereby a myriad of factors govern the connexin life cycle. At the transcriptional level, most attention has yet been paid to the classical cis/ trans machinery (i.e. the interaction between transcription factors and regulatory elements in connexin gene promoter regions) as a gatekeeper of connexin expression. In the last few years, it has become clear that epigenetic processes are also essentially involved in connexin gene transcription. Major determinants of the epigenome include histone modifications and DNA methylation, and recently, microRNA species have also been described as key regulators of the epigenetic machinery. In the present paper, the emerging roles of epigenetic events in the control of connexin expression, and consequently of gap junctional intercellular communication, are reviewed. Besides an updated theoretical background concerning gap junctions and epigenetic phenomena, we provide an in-depth overview of their interrelationship and we demonstrate the clinical relevance of the topic.
Keywords: Abbreviations; 4-Me; 2; N-BAVAH; 5-(4-dimethylaminobenzoyl)aminovaleric acid hydroxamide; 4-PB; 4-phenylbutyrate; AP1; activator protein 1; ATP; adenosine trisphosphate; BRMS1; breast cancer metastasis suppressor 1; cAMP; cyclic adenosine monophosphate; CBP; CREB-binding protein; CL; cytoplasmic loop; CpG; cytosine–guanine; CT; cytoplasmic carboxy tail; Cx; connexin; DNMT; DNA methyltransferase; DNMTi; DNA methyltransferase inhibitor(s); EL1–2; extracellular loop 1–2; ERK1/2; extracellular signal-regulated kinase 1/2; GJIC; gap junctional intercellular communication; HAT; histone acetyltransferase; HDAC(s); histone deacetylase(s); HDACi; histone deacetylase inhibitor(s); HMBA; hexamethylene bisacetamide; IP; 3; inositol trisphosphate; MAPK; mitogen-activated protein kinase; MBP; methylated DNA-binding protein(s); MeCP2; methyl-CpG-binding protein 2; miRNA(s); microRNA(s); mRNA(s); messenger RNA(s); NaB; sodium butyrate; NAD; +; nicotinamide adenine dinucleotide; ncRNA(s); non-coding RNA(s); NT; cytoplasmic amino tail; PKA; protein kinase A; PKC; protein kinase C; pre-miRNA(s); precursor microRNA(s); pri-miRNA; primary microRNA; REST; RE-1 silencing transcription factor; RISC; RNA-induced silencing complex; SAHA; suberoylanilide hydroxamic acid; siRNA; small interfering RNA; Sp1; specificity protein 1; TM1–4; membrane-spanning domain 1–4; TSA; Trichostatin A; UTR(s); untranslated region(s)Gap junction; Connexin; Histone acetylation; DNA methylation; MicroRNA
Epigenetic regulation of gap junctional intercellular communication: More than a way to keep cells quiet?
by Mathieu Vinken; Evelien De Rop; Elke Decrock; Elke De Vuyst; Luc Leybaert; Tamara Vanhaecke; Vera Rogiers (pp. 53-61).
The establishment of gap junctional intercellular communication is a prerequisite for appropriate control of tissue homeostasis. Gap junctions consist of connexin proteins, whereby a myriad of factors govern the connexin life cycle. At the transcriptional level, most attention has yet been paid to the classical cis/ trans machinery (i.e. the interaction between transcription factors and regulatory elements in connexin gene promoter regions) as a gatekeeper of connexin expression. In the last few years, it has become clear that epigenetic processes are also essentially involved in connexin gene transcription. Major determinants of the epigenome include histone modifications and DNA methylation, and recently, microRNA species have also been described as key regulators of the epigenetic machinery. In the present paper, the emerging roles of epigenetic events in the control of connexin expression, and consequently of gap junctional intercellular communication, are reviewed. Besides an updated theoretical background concerning gap junctions and epigenetic phenomena, we provide an in-depth overview of their interrelationship and we demonstrate the clinical relevance of the topic.
Keywords: Abbreviations; 4-Me; 2; N-BAVAH; 5-(4-dimethylaminobenzoyl)aminovaleric acid hydroxamide; 4-PB; 4-phenylbutyrate; AP1; activator protein 1; ATP; adenosine trisphosphate; BRMS1; breast cancer metastasis suppressor 1; cAMP; cyclic adenosine monophosphate; CBP; CREB-binding protein; CL; cytoplasmic loop; CpG; cytosine–guanine; CT; cytoplasmic carboxy tail; Cx; connexin; DNMT; DNA methyltransferase; DNMTi; DNA methyltransferase inhibitor(s); EL1–2; extracellular loop 1–2; ERK1/2; extracellular signal-regulated kinase 1/2; GJIC; gap junctional intercellular communication; HAT; histone acetyltransferase; HDAC(s); histone deacetylase(s); HDACi; histone deacetylase inhibitor(s); HMBA; hexamethylene bisacetamide; IP; 3; inositol trisphosphate; MAPK; mitogen-activated protein kinase; MBP; methylated DNA-binding protein(s); MeCP2; methyl-CpG-binding protein 2; miRNA(s); microRNA(s); mRNA(s); messenger RNA(s); NaB; sodium butyrate; NAD; +; nicotinamide adenine dinucleotide; ncRNA(s); non-coding RNA(s); NT; cytoplasmic amino tail; PKA; protein kinase A; PKC; protein kinase C; pre-miRNA(s); precursor microRNA(s); pri-miRNA; primary microRNA; REST; RE-1 silencing transcription factor; RISC; RNA-induced silencing complex; SAHA; suberoylanilide hydroxamic acid; siRNA; small interfering RNA; Sp1; specificity protein 1; TM1–4; membrane-spanning domain 1–4; TSA; Trichostatin A; UTR(s); untranslated region(s)Gap junction; Connexin; Histone acetylation; DNA methylation; MicroRNA
Molecular mechanisms of endocrine resistance and their implication in the therapy of breast cancer
by Marinella Zilli; Antonino Grassadonia; Nicola Tinari; Alessia Di Giacobbe; Simona Gildetti; Jamara Giampietro; Clara Natoli; Stefano Iacobelli (pp. 62-81).
The use of endocrine agents is a safe and effective treatment in the management of hormone-sensitive breast cancer. Unfortunately, sooner or later, tumor cells develop resistance to endocrine manipulation making useless this approach. During the last decade, new molecules and intracellular signaling pathways involved in endocrine resistance have been identified. Several studies have documented that estrogen receptor signaling may maintain a pivotal role in the tumor growth despite the failure of a previous hormonal treatment.In this review we will discuss the general principles for optimizing the choice of endocrine therapy based on an understanding of the molecular mechanisms responsible for resistance to the different anti-hormonal agents.
Keywords: Endocrine resistance; Breast cancer; Estrogen receptor; Hormonal therapy
Molecular mechanisms of endocrine resistance and their implication in the therapy of breast cancer
by Marinella Zilli; Antonino Grassadonia; Nicola Tinari; Alessia Di Giacobbe; Simona Gildetti; Jamara Giampietro; Clara Natoli; Stefano Iacobelli (pp. 62-81).
The use of endocrine agents is a safe and effective treatment in the management of hormone-sensitive breast cancer. Unfortunately, sooner or later, tumor cells develop resistance to endocrine manipulation making useless this approach. During the last decade, new molecules and intracellular signaling pathways involved in endocrine resistance have been identified. Several studies have documented that estrogen receptor signaling may maintain a pivotal role in the tumor growth despite the failure of a previous hormonal treatment.In this review we will discuss the general principles for optimizing the choice of endocrine therapy based on an understanding of the molecular mechanisms responsible for resistance to the different anti-hormonal agents.
Keywords: Endocrine resistance; Breast cancer; Estrogen receptor; Hormonal therapy
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