The Early Detection of Second Primary Lung Cancers by Sputum Immunostaining

Tockman, Melvyn S.; Erozan, Yener S.; Gupta, Prabodh K.; Piantadosi, Steven; Mulshine, James L.; Ruckdeschel, John C.

doi:10.1378/chest.106.6_supplement.385s

Cited by 54 publications

(19 citation statements)

References 11 publications

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“…Although the detailed mechanisms through which SF2/ASF promotes transformation are understood only in part (30), an improper cellular localization of SF2/ASF may be one of the ways through which it exerts its oncogenic activity, especially due to its regulatory roles in multiple posttranscriptional events in both the nucleus and the cytoplasm. For example, in sputum, an increase in the cytoplasmic levels of another splicing factor, hnRNP A2, serves as a powerful predictor of lung cancer almost a year prior to clinical detection (57), suggesting that such a change may be a prerequisite for the transformation of lung epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Arginine Methylation Controls the Subcellular Localization and Functions of the Oncoprotein Splicing Factor SF2/ASF

Sinha

Allemand

Zuo

et al. 2010

Molecular and Cellular Biology

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Alternative splicing and posttranslational modifications (PTMs) are major sources of protein diversity in eukaryotic proteomes. The SR protein SF2/ASF is an oncoprotein that functions in pre-mRNA splicing, with additional roles in other posttranscriptional and translational events. Functional studies of SR protein PTMs have focused exclusively on the reversible phosphorylation of Ser residues in the C-terminal RS domain. We confirmed that human SF2/ASF is methylated at residues R93, R97, and R109, which were identified in a global proteomic analysis of Arg methylation, and further investigated whether these methylated residues regulate the properties of SF2/ASF. We show that the three arginines additively control the subcellular localization of SF2/ASF and that both the positive charge and the methylation state are important. Mutations that block methylation and remove the positive charge result in the cytoplasmic accumulation of SF2/ASF. The consequent decrease in nuclear SF2/ASF levels prevents it from modulating the alternative splicing of target genes, results in higher translation stimulation, and abrogates the enhancement of nonsense-mediated mRNA decay. This study addresses the mechanisms by which Arg methylation and the associated positive charge regulate the activities of SF2/ASF and emphasizes the significance of localization control for an oncoprotein with multiple functions in different cellular compartments.Pre-mRNA splicing is a required step for the expression of most human genes. Alternative splicing plays a key role in regulating gene expression and is a major source of protein isoform diversity. SR proteins are a family of closely related and highly expressed eukaryotic RNA-binding proteins that regulate both general and alternative splicing (22) and have additional roles in other aspects of gene expression (41). SF2/ ASF, a prototypical member of the SR protein family, has a modular structure with two RNA recognition motifs (RRMs), which recognize a 7-nucleotide exonic splicing enhancer (ESE) motif on pre-mRNA, and an RS domain with numerous repeats of serine-arginine dipeptides (Fig. 1A). SF2/ASF is required for general splicing, though sometimes interchangeably with other SR proteins (33), and also plays a role in the regulation of alternative splicing in a concentration-dependent manner, in part through the recognition of ESEs (16). In addition to its role as a broad-specificity splicing regulator, SF2/ ASF strongly enhances nonsense-mediated mRNA decay (NMD) upon overexpression (65), stimulates translation both in vivo and in vitro in an enhancer-dependent manner (50), and functions as an adaptor protein for mRNA export (26). Some of these additional functions of SF2/ASF reflect its ability to shuttle between the nucleus and the cytoplasm (13). Reflecting its multifaceted role as a regulator in various cellular processes, SF2/ASF is a potent oncoprotein whose overexpression by as little as 2-fold is sufficient to transform immortal rodent fibroblasts (30). Conversely, the knockdown of SF2/...

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Section: Discussionmentioning

confidence: 99%

Arginine Methylation Controls the Subcellular Localization and Functions of the Oncoprotein Splicing Factor SF2/ASF

Sinha

Allemand

Zuo

et al. 2010

Molecular and Cellular Biology

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“…However, hnRNPA2 is mostly nuclear and there it is involved in several functions as splicing and telomere length maintenance (Krecic and Swanson, 1999;Dreyfuss et al, 2002;Ford et al, 2002). A growing number of evidence indicates that hnRNPA2 is overexpressed in a variety of cancers, including tumors from lung, breast and pancreas cancer (Tockman et al, 1997;Zhou et al, 2001;Yan-Sanders et al, 2002;Patry et al, 2003). In some cases, the overexpression of hnRNPA2 has a prognostic value and this protein is now considered to be the lead marker for early diagnosis of lung cancer (Mulshine et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous nuclear ribonucleoprotein A2 is a SET-binding protein and a PP2A inhibitor

et al. 2005

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The oncoprotein SET participates in a diversity of cellular functions including cell proliferation. Its role on cell cycle progression is likely mediated by inhibiting cyclin B-cdk1 and the protein phosphatase 2A (PP2A). On identifying new SET cellular partners, we found that SET interacts in vitro and in vivo with the heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2); a protein involved in various aspects of mRNA biogenesis. The SET-binding region of hnRNPA2 is the RNP1 sequence that belongs to the RNA-binding domain (RBD) of this protein. We also found that hnRNPA2 has much higher affinity for singlestanded DNA than for SET. On analysing the effect of hnRNPA2 on PP2A inhibition by SET, we observed that hnRNPA2 cooperates with SET on PP2A inhibition. This is because we found that hnRNPA2 is also a PP2A inhibitor. HnRNPA2 interacts with PP2A by the RNP1 sequence; however, to inhibit PP2A activity, the complete RBD is needed. We also observed that overexpression of hnRNPA2 inhibits PP2A activity and stimulates cell proliferation. Interestingly, the overexpression of the complete RBD is sufficient to stimulate proliferation. As hnRNPA2 is overexpressed in a variety of human tumors, our results suggest that hnRNPA2 might participate in oncogenesis by stimulating cell proliferation.

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“…Earlier studies showed that lung cancer screening studies with conventional chest X-ray and sputum cytology detected more lung cancers, earlier cancer stages, and smaller tumors, but there was no reduction in late-stage tumors and lung cancer-specific mortality [16,24,25,26,27,28,29,30,31,32,33,34,35]. With its introduction approximately one decade ago, LDCT enhanced the detection of lung cancer [36].…”

Section: Epidemiology and Effectiveness Of Lung Cancer Screening Progmentioning

confidence: 99%

Early Detection of Lung Cancer: A Statement from an Expert Panel of the Swiss University Hospitals on Lung Cancer Screening

et al. 2014

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The discussion about setting up a program for lung cancer screening was launched with the publication of the results of the National Lung Screening Trial, which suggested reduced mortality in high-risk subjects undergoing CT screening. However, important questions about the benefit-harm balance and the details of a screening program and its cost-effectiveness remain unanswered. A panel of specialists in chest radiology, respiratory medicine, epidemiology, and thoracic surgery representing all Swiss university hospitals prepared this joint statement following several meetings. The panel argues that premature and uncontrolled introduction of a lung cancer screening program may cause substantial harm that may remain undetected without rigorous quality control. This position paper focuses on the requirements of running such a program with the objective of harmonizing efforts across the involved specialties and institutions and defining quality standards. The underlying statement includes information on current evidence for a reduction in mortality with lung cancer screening and the potential epidemiologic implications of such a program in Switzerland. Furthermore, requirements for lung cancer screening centers are defined, and recommendations for both the CT technique and the algorithm for lung nodule assessment are provided. In addition, related issues such as patient management, registry, and funding are addressed. Based on the current state of the knowledge, the panel concludes that lung cancer screening in Switzerland should be undertaken exclusively within a national observational study in order to provide answers to several critical questions before considering broad population-based screening for lung cancer.

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The Early Detection of Second Primary Lung Cancers by Sputum Immunostaining

Cited by 54 publications

References 11 publications

Arginine Methylation Controls the Subcellular Localization and Functions of the Oncoprotein Splicing Factor SF2/ASF

Arginine Methylation Controls the Subcellular Localization and Functions of the Oncoprotein Splicing Factor SF2/ASF

Heterogeneous nuclear ribonucleoprotein A2 is a SET-binding protein and a PP2A inhibitor

Early Detection of Lung Cancer: A Statement from an Expert Panel of the Swiss University Hospitals on Lung Cancer Screening

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