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PubMedDate not supplied

Stress pathways in the rat cochlea and potential for protection from acquired deafness.

Noise overstimulation will induce or influence intracellular molecular pathways in the cochlea. One of these is the 'classical' stress response pathway involving heat shock proteins. Hsp70 is induced in the cochlea by a wide variety of stresses including noise, hyperthermia and ototoxic drugs. When a stress that induces Hsp70 is applied to the cochlea, there is protection from a subsequent noise that would normally cause a permanent hearing loss. An upstream regulator of heat shock protein transcription, heat shock factor 1, is expressed in the cochlea and activated by stress. Mice lacking this heat shock factor have reduced recovery from noise-induced hearing loss. The same noise exposure that induces Hsp70 also increases the level of glial cell line-derived neurotrophic factor in the cochlea. Moreover, when this neurotrophic factor is applied into the perilymph of scala tympani prior to a noise exposure there is a significant reduction in hair cell loss and hearing loss. With the potential for activation of multiple pathways in the response to noise, gene microarrays can be useful to examine global gene expression. Initial studies examined differential gene expression immediately following a mild noise exposure (from which there is complete recovery) versus an intense noise (giving profound permanent deafness). Differential expression of several immediate early genes was found following the intense but not the mild noise exposure.

Animals↗
PubMedDate not supplied

Anti-tumor chemotherapy utilizing peptide-based approaches--apoptotic pathways, kinases, and proteasome as targets.

The pharmacological sciences are taking advantage of recent discoveries that have defined the molecular pathways governing apoptosis. These signaling cascades are frequently inactivated or distorted by mutations in cancer cells. Peptides derived from critical interaction, phosphorylation, or cleavage sites are the preferred leads (starting points) for the development of new drugs. In this review we summarize recent peptide-based approaches that target MDM2, p53, NF-kappaB, ErbB2, MAPK, as well as Smac/DIABLO, IAP BIR domains, and Bcl-2 interaction domains, with a specific focus on the BH3 domain. Separate parts of the review deal with proteasome inhibitors, integrin-derived peptides, and molecules that are being tested for tumor-selective delivery of anticancer drugs ("magic bullet" approach). The proteasome inhibitors and integrin-derived peptides show a variety of effects, targeting not only tumor growth, but also angiogenesis, metastasizing potential, and other cancer cell functions. The last part of this review describes approaches that use specific properties (surface receptors, increased enzymatic activities) of cancer cells in order to target them specifically. These new generations of anticancer drugs provide the foundations for therapies with fewer side effects and higher efficacy.

Angiogenesis Inhibitors↗
PubMed2001

Novel pharmacological agents in clinical development for solid tumours.

For decades, cancer therapy has focused on DNA-directed mechanisms of cytotoxicity, utilising agents with limited efficacy and significant toxicity. Recent advances in tumour biology have elucidated the molecular pathways implicated in the pathogenesis and progression of cancers and have resulted in the discovery of a variety of novel molecular targets for therapeutic intervention. Promising novel agents targeting signal transduction pathways, cell cycle regulation, angiogenesis and apoptosis are in clinical testing and are discussed in this review.

Angiogenesis Inhibitors↗
PubMed2005

Global gene expression analysis in the bones reveals involvement of several novel genes and pathways in mediating an anabolic response of mechanical loading in mice.

To identify the genes and signal pathways responsible for mechanical loading-induced bone formation, we evaluated differential gene expression on a global basis in the tibias of C57BL/6J (B6) mice after four days of four-point bending. We applied mechanical loads to the right tibias of the B6 mice at 9 N, 2 Hz for 36 cycles per day, with the left tibias used as unloaded controls. RNA from the tibias was harvested 24 h after last stimulation and subjected to microarray. Of the 20,280 transcripts hybridized to the array, 346 were differentially expressed in the loaded bones compared to the controls. The validity of the microarray data was established with the increased expression of bone-related genes such as pleiotrophin, osteoglycin, and legumain upon four-point bending and confirmation of increased expression of selected genes by real-time PCR. The list of differentially expressed genes includes genes involved in cell growth, differentiation, adhesion, proteolysis, as well as signaling molecules of receptors for growth factors, integrin, Ephrin B2, endothelin, and adhesion G protein coupled receptor. Pathway analyses suggested that 28 out of the 346 genes exhibited a direct biological association. Among the biological network, fibronectin and pleitrophin function as important signaling molecules in regulating periosteal bone formation and resorption in response to four-point bending. Furthermore, some expressed sequence tags (ESTs) with no prior known function have been identified as potential mediators of mechanotransduction signaling pathways. Further studies on these previously unknown genes will improve our understanding of the molecular pathways and mechanisms involved in bone's response to mechanical stress.

Anabolic Agents↗
PubMed2001

Abnormalities of the ARF-p53 pathway in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is associated with heavy smoking and drinking, but the molecular pathway of tumorigenesis is not understood. Inactivation of the p53 tumor suppressor gene is likely to play an important role since p53 mutation is frequently found. The p14ARF tumor suppressor gene is functionally linked to p53, because it is activated by oncogenes and causes p53-dependent growth arrest and apoptosis. The relationship between p14ARF and p53 inactivation has not been described for OSCC. We studied 25 cases of OSCC to determine if there is an inverse correlation between p53 mutation and p14ARF inactivation by homozygous deletion or mutation. p53 mutation was found in 16 of 25 cases (64%), including nine missense and seven truncating mutations. While all cases with missense mutations showed abnormal accumulation of p53 protein, there were also five carcinomas which showed increased p53 staining in the absence of mutation. p14ARF deletion or mutation was found in eight cases (32%), six of which also demonstrated p53 mutation. Our findings indicate that OSCC often involves loss of both p14ARF and p53 function and suggest that inactivation of these two tumor suppressor genes are not functionally equivalent during tumorigenesis.

Adult↗
PubMed2006

Overexpression of PKD1 causes polycystic kidney disease.

The pathogenetic mechanisms underlying autosomal dominant polycystic kidney disease (ADPKD) remain to be elucidated. While there is evidence that Pkd1 gene haploinsufficiency and loss of heterozygosity can cause cyst formation in mice, paradoxically high levels of Pkd1 expression have been detected in the kidneys of ADPKD patients. To determine whether Pkd1 gain of function can be a pathogenetic process, a Pkd1 bacterial artificial chromosome (Pkd1-BAC) was modified by homologous recombination to solely target a sustained Pkd1 expression preferentially to the adult kidney. Several transgenic lines were generated that specifically overexpressed the Pkd1 transgene in the kidneys 2- to 15-fold over Pkd1 endogenous levels. All transgenic mice reproducibly developed tubular and glomerular cysts and renal insufficiency and died of renal failure. This model demonstrates that overexpression of wild-type Pkd1 alone is sufficient to trigger cystogenesis resembling human ADPKD. Our results also uncovered a striking increased renal c-myc expression in mice from all transgenic lines, indicating that c-myc is a critical in vivo downstream effector of Pkd1 molecular pathways. This study not only produced an invaluable and first PKD model to evaluate molecular pathogenesis and therapies but also provides evidence that gain of function could be a pathogenetic mechanism in ADPKD.

Animals↗
PubMed2004

Mouse strain-specific differences in vascular wall gene expression and their relationship to vascular disease.

OBJECTIVE: Different strains of inbred mice exhibit different susceptibility to the development of atherosclerosis. The C3H/HeJ and C57Bl/6 mice have been used in several studies aimed at understanding the genetic basis of atherosclerosis. Under controlled environmental conditions, variations in susceptibility to atherosclerosis reflect differences in genetic makeup, and these differences must be reflected in gene expression patterns that are temporally related to the development of disease. In this study, we sought to identify the genetic pathways that are differentially activated in the aortas of these mice. METHODS AND RESULTS: We performed genome-wide transcriptional profiling of aortas from C3H/HeJ and C57Bl/6 mice. Differences in gene expression were identified at baseline as well as during normal aging and longitudinal exposure to high-fat diet. The significance of these genes to the development of atherosclerosis was evaluated by observing their temporal pattern of expression in the well-studied apolipoprotein E model of atherosclerosis. CONCLUSIONS: Gene expression differences between the 2 strains suggest that aortas of C57Bl/6 mice have a higher genetic propensity to develop inflammation in response to appropriate atherogenic stimuli. This study expands the repertoire of factors in known disease-related signaling pathways and identifies novel candidate genes for future study. To gain insights into the molecular pathways that are differentially activated in strains of mice with varied susceptibility to atherosclerosis, we performed comprehensive transcriptional profiling of their vascular wall. Genes identified through these studies expand the repertoire of factors in disease-related signaling pathways and identify novel candidate genes in atherosclerosis.

Aging↗
PubMed2006

Magnetic resonance imaging of tumor physiology.

Cancer is one of the most mutable diseases known, exhibiting a superfluity and heterogeneity of molecular pathways that impart an almost chimerical nature to it. Exploiting these pathways for patient therapy demands an understanding of the physiology of tumors from the molecular to the systemic level. To this end, multiparametric functional and molecular imaging play a vital role in not only tracking delivery and efficacy of therapy, but also in discovering novel therapeutic targets. The plethora of available magnetic resonance (MR) contrast mechanisms, in conjunction with its superior dynamic functional range, bestow on magnetic resonance imaging (MRI) the potential to be a formidable tool in the noninvasive, in vivo, multilevel assessment of tumor physiology. This chapter begins with a description of the aberrant pathophysiology of tumors, including a description of tumor angiogenesis and how MRI affords us a window into such processes. Following a discussion of endogenous and exogenous contrast, a specific example of measuring a tumor's vascular parameters with a macromolecular contrast agent is considered. This is followed by a description of revolutionary developments in the molecular imaging of tumors with MRI and complementary modalities.

Animals↗
PubMed2003

Polycythemia vera: a comprehensive review and clinical recommendations.

More than a century has elapsed since the appearance of the modern descriptions of polycythemia vera (PV). During this time, much has been learned regarding disease pathogenesis and PV-associated molecular aberrations. New information has allowed amendments to traditional diagnostic criteria. Phlebotomy remains the cornerstone treatment of PV, whereas myelosuppressive agents may augment the benefit of using phlebotomy for thrombosis prevention in high-risk patients. Excessive aspirin use is contraindicated in PV, although the use of lower-dose aspirin has been shown to be safe and effective in alleviating microvascular symptoms including erythromelalgia and headaches. Recent studies have shown the utility of selective serotonin receptor antagonists for treating PV-associated pruritus. Nevertheless, many questions remain unanswered. What is the specific genetic mutation or altered molecular pathway that is causally related to the disease? In the absence of a specific molecular marker, how is a working diagnosis of PV made? What evidence supports current practice in the management of PV? This article summarizes both old and new information on PV; proposes a modern diagnostic algorithm to formulate a working diagnosis; and provides recommendations for patient management, relying whenever possible on an evidence-based approach.

Algorithms↗
PubMed1999

Activation of tyrosine kinases by alpha1A-adrenergic and growth factor receptors in transfected PC12 cells.

We compared the role of tyrosine kinases in alpha(1A)-adrenergic receptor (AR) and growth factor receptor stimulation of mitogen-activated protein kinase pathways in PC12 cells. Norepinephrine (NE) (noradrenaline), epidermal growth factor (EGF) and nerve growth factor (NGF) caused different patterns of tyrosine phosphorylation in PC12 cells stably expressing alpha(1A)-ARs. NE increased tyrosine phosphorylation of focal adhesion-related kinase Pyk2 and a 70 kDa protein, probably paxillin, whereas EGF strongly stimulated tyrosine phosphorylation of the EGF receptor and cytokine-activated kinase Jak2. The EGF receptor inhibitor AG1478 inhibited activation of extracellular signal-regulated kinases (ERKs) by EGF but not by NE. EGF and NGF strongly activated tyrosine phosphorylation of Shc and caused association of Src-homology collagen (Shc) with growth-factor-receptor-bound protein 2 (Grb2); however, neither NE nor UTP caused substantial activation of the Shc/Grb2 pathway. NE, UTP, EGF and NGF all increased tyrosine phosphorylation of Src, and this was inhibited by the Src inhibitor PP2. However, PP2 inhibited ERK activation in response to NE and UTP, but not in response to EGF or NGF. PP2 also completely blocked NE-induced PC12 cell differentiation, but had no measurable effect on NGF-induced differentiation. These studies show that activation of mitogen-activated protein kinase pathways by G-protein-coupled receptors and tyrosine kinase receptors proceed through distinct molecular pathways in PC12 cells, and support an obligatory role for Src activation in mitogenic responses to alpha(1A)-ARs in these cells.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Genetic alterations in Barrett's esophagus and esophageal adenocarcinoma.

Barrett's esophagus and esophageal adenocarcinoma are increasing health problems in the Western world. The rise in incidence of esophageal adenocarcinoma is greater than that for any other malignancy in Caucasian populations. The social impact of the disease is stressed in addition by the very aggressive nature of esophageal adenocarcinomas with 5-year survival rates of less than 25%. Far more people develop the premalignant condition Barrett's metaplasia than high grade dysplasia and invasive carcinoma. This means that fortunately not all patients with Barrett's metaplasia will make the progression to high grade disease. It is hoped that by unravelling the molecular mechanisms involved in the neoplastic transformation in Barrett's esophagus it will become possible to predict disease progression in the individual patient. This would be a major step forward in the curative treatment of this disease. In addition, identification of the crucial molecular pathways involved in esophageal adenocarcinogenesis would facilitate the development of new treatment strategies. The molecular mechanisms underlying the initiation and progression of this disease are largely unknown. In this review the histological sequence of Barrett's metaplasia via dysplasia to adenocarcinoma is introduced; then the general molecular concepts of carcinogenesis are explained. Furthermore, the most important esophageal neoplasia related genes are described including their possible role in the neoplastic process. The frequent genomic aberrations are put in relation to the different histological entities. Finally, as future prospect, a molecular grading of esophageal adenocarcinogenesis is anticipated.

Adenocarcinoma↗
PubMed1995

Molecular genetics and cytogenetics of sarcomas.

It was only 25 years ago that the concept of cancer as a genetic disease began to gain widespread acceptance. It is encouraging to note that recurrent molecular pathways critical to the genesis and evolution of human sarcomas are being elucidated through molecular and cytogenetic techniques. It is also important to remember that molecular genetics and cytogenetics are still in their infancy. In this review, we have barely touched on the tremendous amount of information that has developed in sarcoma genetics and cytogenetics. As this synergistic evolution of genetic changes in human sarcomas becomes better understood, new and better therapeutic strategies aimed at circumventing these processes will be developed. But the biologic and genetic redundancies intrinsic to mammalian cells continue to allow tumors to adapt and resist chemotherapeutic agents. Understanding sarcoma progression at the molecular level will allow, therefore, for the identification of better diagnostic markers, the development of new therapeutic strategies, and the ability to select the most effective and least toxic combination of antitumor therapies for a patient.

Genes, Retinoblastoma↗
PubMed1998

Anti-VLA4/VCAM-1-induced mobilization requires cooperative signaling through the kit/mkit ligand pathway.

Although a large body of data on mobilization have yielded valuable clues, the mechanism(s) dictating egress of stem/progenitor cells during baseline hematopoiesis and after their mobilization are poorly understood. We have previously provided functional in vivo evidence that cytoadhesion molecules, specifically the beta1 integrins, are involved in mobilization; however, the mechanism by which this was achieved was unclear. To provide further insights into the anti-very late antigen 4 (VLA4)/anti-vascular cell adhesion molecule 1 (VCAM-1)-induced mobilization, we used these antibodies to treat mutant mice with compromised growth factor receptor function. We found that mobilization by anti-VLA4 does not depend on a functional granulocyte colony-stimulating factor, interleukin-7 (IL-7), or IL-3alpha receptor. By contrast, the functional kit receptor is required, because W/Wv mice responded minimally, whereas Steel-Dickie (Sl/Sld) responded normally. Both Wv and Sl/Sld mice did not respond to anti-VCAM-1 treatment, in contrast to their +/+ littermates and despite normal levels of VCAM-1 expression in bone marrow cells. The defective response to anti-VCAM-1 in W/Wv mice was corrected after their transplantation with +/+ cells. mev/mev mice showed increased numbers of circulating progenitors before treatment and a heightened response after anti-VLA4 or anti-VCAM-1 treatment. Downmodulation of kit expression was detected in normal bone marrow cells after anti-VLA4 treatment. On the strength of the above findings we conclude that (1) anti-VLA4/VCAM-1-induced mobilization likely requires signaling for stimulation of cell migration; (2) this cooperative signaling involves the kit/kit ligand pathway, and provides a novel example of integrin/cytokine crosstalk; and (3) migration mediated through the kit/kit ligand pathway may be a common contributor to different mobilization stimuli. Dissection of the exact molecular pathways that lead to mobilization remains a future challenge.

Animals↗
PubMed2003

Basal cell carcinoma: a dermatopathological and molecular biological update.

The ideal classification of basal cell carcinoma (BCC) should be able to identify subtypes which correlate with clinical behaviour and treatment requirements. Unfortunately, however, such a classification has yet to be defined. In the interim, the currently most favoured classification is one based predominantly on histological growth pattern. This classification contributes to the useful concept of low- and high-risk histological subtypes of BCC. The latter are characterized by an increased probability of subclinical extension and/or incomplete excision and/or aggressive local invasive behaviour and/or local recurrence. The Royal College of Pathologists has published a minimum dataset for the histopathological reporting of BCC and this has been written to be compatible with the British Association of Dermatologists' management guidelines. Growth patterns to be reported include nodular, superficial, infiltrative/morphoeic and micronodular types, together with differentiation when of severely atypical or malignant squamous type (basosquamous carcinoma). Deep and peripheral excision margins will be reported to be either involved or clear. The latter will include a comment of a clearance of less than 1 mm for close margins and a measured distance in whole millimetres for other excisions. Clinical assessment and histology remain the 'gold standard' for evaluating BCC and cancers in general. However, in the postgenomic era emphasis is changing from the gathering and archiving of genomic data to its analysis and use in guiding clinical practice. In this context, a current goal is to define cancer phenotype in terms of molecular abnormalities and use this as a new gold standard. One way to assess whether this goal is being achieved for BCC is to determine whether our knowledge of its molecular pathology has any relevance to the minimum dataset for histological reporting. Knowledge of BCC molecular pathology has been fuelled by the recent discovery that deregulation of the Hedgehog (Hh) signalling pathway, a key player in embryonic patterning, appears to be fundamental to tumour growth. But despite accrual of a large amount of data concerning Hh pathway molecular alterations in neoplasia, little is known about the functional consequences of these changes in BCC, how they lead to tumour development, or how they relate to non-Hh pathway alterations such as TP53 mutation. Recent work suggests that the cellular localization of beta-catenin gives a degree of credence to the growth pattern classification of BCC. Furthermore, it is possible that beta-catenin may have a pathogenetic role in the invasive behaviour of BCC. This review draws on current evidence to discuss these issues and assess whether they are relevant to the minimum dataset.

Basal Cell Carcinoma↗
PubMed1997

[Apoptosis and anti-apoptosis genes in the Bcl-2 family].

Apoptosis, or programmed cell death, is an active process of self-destruction, described a long time ago. However, the understanding of the molecular pathways which regulate programmed cell death is more recent and far from complete. Apoptosis occurs during embryonic and foetal development, and tissue remodeling, and its purpose is to assure homeostasis of cells and tissues. Apoptosis-defining morphological and biochemical changes are now well documented. Many physiological and non-physiological factors have been described as inducers of apoptosis. Several genes affecting various steps in programmed cell death must be expressed to trigger apoptosis. For example, ced-3 and ced-4 in the nematode C. elegans, and ICE, a gene found in mammals. In addition, the existence of genes suppressing apoptosis, like the human bcl-2 gene and a family of related bcl-2 genes was recently described. Several data dealing with these family of anti-apoptotic genes and some of their mechanisms of action are now currently available. It is clear that bcl-2 protects many cell lines from induced apoptosis. Other proteins, like bcl-xL, A1 or mcl-1 have the same anti-apoptotic function, but several molecules of the same family, like bcl-xS, bax-alpha or bak can trigger the opposite effect. It is known that bcl-2 can interact with other proteins. For example, bax, which can exist as a homodimer, is also able to form a heterodimer with bcl-2. A surexpression of bax in several cell lines allows to counteract the effect of bcl-2. R-ras p23 is another example, among others, of a protein interacting with bcl-2, and this results in an interruption of the apoptotic signal transduction pathway when bcl-2 is overexpressed. Some other explanations allowing a more detailed analysis of the molecular mechanisms of apoptosis and anti-apoptosis are discussed in this short review. Many interesting results suggest that bcl-2 is a death repressor molecule functioning in an anti-oxydant pathway, but other recent data seem to claim the contrary. Recently, the demonstration was made that apoptosis may require the activation of several classes of proteases. It seems now that bcl-2 has also a function of protease(s) inhibitor.

Animals↗
PubMed2004

Oral graft-versus-host disease and programmed cell death: pathogenetic and clinical correlates.

Graft-versus-host disease (GVHD) is an untoward complication of bone marrow transplantation. It is characterized by an immune-mediated attack by donor immune cells against various host cells and tissues, a process which may be associated with significant morbidity in affected patients. Oral lesions are a common sequelae and can serve as a highly predictive index to the presence of systemic GVHD. The oral lesions of GVHD are clinically and histologically lichenoid in nature and can be a challenge in terms of management. Ulcerated and painful mucosal lesions may represent a significant impediment to normal eating habits and nutritional intake, necessitating appropriate diagnosis and treatment. Importantly, recent evidence has indicated that programmed cell death, or apoptosis, is the major constituent in the pathogenesis of GVHD. Apoptosis not only plays a major role in normal growth and ontogeny, but has been shown to contribute to a wide spectrum of both inflammatory and neoplastic disorders. Since knowledge of apoptotic molecular pathways is requisite for understanding GVHD, the purpose of this paper is to provide a fundamental overview of the predominant apoptotic mechanisms implicated in the pathogenesis of GVHD and to relate these findings to the oral complications of the disease. Finally, we will discuss management strategies for diagnosing and treating the oral lesions of GVHD. By explicating the molecular events in the apoptotic pathway, unique therapeutic and pharmacologic strategies for regulating apoptosis may be developed in the future, reducing the morbidity associated with conditions like GVHD.

Apoptosis↗
PubMed2001

Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc-dependent pathway.

T lymphocytes circulate in a quiescent state until they encounter cognate antigen bound to the surface of an antigen-presenting cell. The molecular pathways that regulate T cell quiescence remain largely unknown. Here we show that forced expression of the lung Krüppel-like transcription factor (LKLF) in Jurkat T cells is sufficient to program a quiescent phenotype characterized by decreased proliferation, reduced cell size and protein synthesis and decreased surface expression of activation markers. Conversely, LKLF-deficient peripheral T cells produced by gene targeting showed increased proliferation, increased cell size and enhanced expression of surface activation markers in vivo. LKLF appeared to function, at least in part, by decreasing expression of the proto-oncogene encoding c-Myc. Forced expression of LKLF was associated with markedly decreased c-Myc expression. In addition, many effects of LKLF expression were mimicked by expression of the dominant-negative MadMyc protein and rescued by overexpression of c-Myc. Thus, LKLF is both necessary and sufficient to program quiescence in T cells and functions, in part, by negatively regulating a c-Myc--dependent pathway.

Cell Division↗
PubMed2006

Mechanisms of disease: the role of heat-shock protein 90 in genitourinary malignancy.

Insight into the molecular biology of cancer has allowed the development of novel therapeutic strategies that target specific oncogenic pathways. Molecular therapeutic strategies are now part of the armamentarium available against urologic malignancy. Among the many targets of interest in urologic cancer, heat-shock protein 90 (HSP90) shows great promise. This molecule has a major role in prostate as well as in renal malignancy. In contrast to other targets, where cancer might escape inhibition via alternative pathways, HSP90 operates at multiple checkpoints in a cancer cell. Its inhibition could, therefore, prove more difficult for neoplastic cells to overcome. Inhibitors of HSP90, such as geldanamycin and its derivatives (17-allylamino-17-demethoxygeldanamycin and 17-dimethylaminoethylamino-17-demethoxygeldanamycin, known as 17AAG and 17DMAG, respectively) are available and have shown activity both in vivo and in vitro. 17AAG is currently being tested for efficacy in humans after having completed phase I trials, while 17DMAG is still in phase I evaluation. Phase II trials of HSP90 inhibitors in urologic malignancy are being conducted in kidney and advanced prostate cancer. Beyond monotherapy, HSP90 inhibitors might also prove to be beneficial in combination therapy with other chemotherapeutic agents in advanced disease. Studies being conducted in prostate cancer will hopefully help to define this potential application better.

Antineoplastic Agents↗