Biomedical subjects

L M Wang

Publications and source records attributed to L M Wang.

At least 37 records · Page 2Linked to original sources

PubMed2000

Sigma-2 receptors as a biomarker of proliferation in solid tumours.

Over the past several years, our group has provided considerable evidence that the expression of sigma-2 (sigma2) receptors may serve as a biomarker of tumour cell proliferation. In these in vitro studies, sigma2 receptors were expressed 8-10 times more in proliferative (P) tumour cells than in quiescent (Q) tumour cells, and the extent and kinetics of their expression were independent of a number of biological, physiological and environmental factors often found in solid tumours. Moreover, the expression of sigma2 receptors followed both the population growth kinetics when Q-cells were recruited into the P-cell compartment and the proliferative status of human breast tumour cells treated with cytostatic concentrations of tamoxifen. However, these in vitro studies may or may not be indicative of what might occur in solid tumours. In the present study, the sigma2 receptor P:Q ratio was determined for the cells from subcutaneous 66 (diploid) and 67 (aneuploid) tumours grown in female nude mice. The sigma2 receptor P:Q ratio of the 66 tumours was 10.6 compared to the sigma2 receptor P:Q ratio of 9.5 measured for the 66 tissue culture model. The sigma2 receptor P:Q ratio of the 67 tumours was 4.5 compared to the sigma2 receptor P:Q ratio of approximately equal 8 measured for the 67 tissue culture model. The agreement between the solid tumour and tissue culture data indicates that: (1) the expression of sigma2 receptors may be a reliable biomarker of the proliferative status of solid tumours and (2) radioligands with both high affinity and high selectivity for sigma2 receptors may have the potential to non-invasively assess the proliferative status of human solid tumours using imaging techniques such as positron emission tomography or single-photon emission computerized tomography.

Animals↗

PubMed2000

Spectral analysis of systemic arterial pressure and heart rate signals of patients with acute respiratory failure induced by severe organophosphate poisoning.

OBJECTIVE: Spectral analysis of systemic arterial pressure (BP) and heart rate (HR) signals may be an alternative prognostic tool for predicting patient outcome in the intensive care unit (ICU). We evaluated the applicability of the same analysis in the emergency department for predicting mortality in patients with acute respiratory failure induced by severe organophosphate poisoning. DESIGN: Prospective collection of data from 14 emergency service patients. SETTING: Emergency service at a large, university-affiliated medical center. PATIENTS: Consecutive patients who, after attempting suicide by ingesting organophosphates, were admitted to the ICU of the emergency service with acute respiratory failure and remained for > or =2 days INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic and survival data and day 1 Acute Physiology and Chronic Health Evaluation (APACHE) II and Glasgow Coma Scale scores were recorded. Continuous, on-line, real-time spectral analysis of BP and HR signals was carried out during the first 12 hrs after admission. We then computed the total sum of power density during this period of the low-frequency (0.04-0.15 Hz) and very low-frequency (0.004-0.04 Hz) components in the BP and HR spectra, along with the averaged values of mean BP and HR. Eight patients who recovered exhibited vigorous power in the low-frequency and very low-frequency components of their BP and HR signals. There was a significant reduction in the power density of those four spectral components in three patients who eventually died. Three patients discharged in a vegetative state manifested significantly reduced power in the low-frequency component in their BP spectra, with maintained power in the other three spectral components. APACHE II and Glasgow Coma Scale scores of the recovered patients were discernibly different from those of patients who eventually died or who became vegetative. None of the 14 patients showed appreciable differences in mean BP, mean HR, erythrocyte or plasma cholinesterase concentration, or atropine requirement during the first 24 hrs. CONCLUSION: The low-frequency and very low-frequency components of BP and HR signals may be a sensitive alternative index for early prediction of mortality in patients with acute respiratory failure induced by severe organophosphate poisoning.

Acute Disease↗

PubMed2000

The effect of the prostaglandin I2 analogue OP-2507 on adrenaline-induced pulmonary edema in rabbits and analysis of hemodynamic changes.

This study was carried out to understand the onset mechanism of adrenaline (ADR)-induced pulmonary edema (PE) and the effect of drugs related to the arachidonate cascade in a rabbit model. ADR was administered intravenously by a bolus injection to the rabbits at 50, 75 and 100 microg/kg. To evaluate the severity of PE, the lung-water ratio (LWR) was calculated as a ratio of the difference between wet and dry lung weight to dry lung weight. The PE incidence and LWR exhibited a dose-dependent increase, and LWR correlated with the left atrial pressure (LAP). The involvement of the arachidonate cascade was evaluated by the co-administration of flurbiprofen, a cyclooxygenase inhibitor; ozagrel, a thromboxane synthase inhibitor; and OP-2507 (15-cis-(4-n-propylcyclohexyl)-6,17,18, 19,20-pentanor-9-deoxy-6,9-alpha-nitriloprostaglandin F1 methyl ester), a prostaglandin I2 analogue. Co-treatment of the rabbits with ADR and flurbiprofen resulted in an increase in LAP and the incidence of PE, whereas co-administration of ozagrel did not exhibit any significant changes in the measured parameters. Conversely, OP-2507 reduced the LAP, PE incidence and LWR when co-administered with ADR. Rabbits co-treated with OP-2507 displayed an improved cardiac function. The results of these studies demonstrated the effectiveness of OP-2507 in protecting the lung and cardiac function from the ADR-induced PE.

Animals↗

PubMed2000

Klebsiella pneumoniae renal abscess.

BACKGROUND: The clinical characteristics of renal abscess caused by Klebsiella pneumoniae have not been previously reported in case-series studies. The purpose of this study is to demonstrate the clinical characteristics of K pneumoniae renal abscess for early diagnosis and to identify the clinical risk factors associating with poor prognosis. METHODS: We retrospectively reviewed the medical records of 24 patients with K pneumoniae renal abscess, from April, 1982 through February, 1998. The clinical presentations, including the demographic characteristics, predisposing disorders, initial signs and symptoms, laboratory test results, diagnostic radiology studies, therapeutic modalities and risk factors associated with mortality were studied. RESULTS: The mean age was 58.7 years and the male to female ratio was 10:14. The most common predisposing factors were diabetes mellitus (58%), urolithiasis (25%) and immunosuppression (17%). Fever, chills and flank pain were the most common symptoms and signs, whereas pyuria, elevation of leukocyte count, glucose, blood urea nitrogen and creatinine were the common laboratory features. The distinct complications of K pneumoniae renal abscess were bacteremia in 13 (54%), emphysematous pyelonephritis in five (21%), and metastatic septic infection in three (12.5%). The cure rate was 52% (11/21) in patients treated with a combination of antibiotics and percutaneous drainage; however, six (35%) patients who survived required another surgical procedure for complete recovery. The overall mortality rate was 25%. The clinical factors of elderly age (>65 years) at presentation, lethargy, elevation of serum blood urea nitrogen and pulmonary complications were associated with poor prognoses. CONCLUSIONS: Focusing on the early diagnosis of K pneumoniae renal abscess and recognition of the prognostic factors for a poor prognosis, we highlight the specific clinical characteristics that include elderly age, lethargy, impairment of renal function, metastatic septic lesions and pulmonary complications. All patients with K pneumoniae renal abscesses should receive empiric antibiotics and percutaneous drainage or aspiration, and surgical intervention as necessary for patients with intractable disease.

Abscess↗

PubMed2000

[Responses induced by dopamine in Xenopus laevis oocytes injected with mRNA from heat injured rat striatum].

Poly(A)(+) mRNA isolated from the striatum of normal rats and heat injured rats by RNAgents Total RNA Isolation System and PolyTract mRNA RNAgents Isolation Systems was microinjected into Xenopus laevis oocytes to express functional neurotransmitter receptors. Membrane currents were recorded by the conventional patch clamp technique for measuring the relative amounts of mRNA encoding dopamine receptor in order to study the change in dopamine receptors in heat injured rat striatum. There was no change in resting membrane potentials of the oocytes before and after mRNA injection. Dopamine induced membrane currents were shown to be mediated through Cl( ). The oocytes injected with mRNA from heat injured rat striatum were less sensitive to dopamine than those injected with mRNA from normal rats ( P<0.05). The above result showed that heat injury affected gene expression and signal transduction of dopamine receptors in rat striatum.

Animals↗

PubMed1999

Insulin receptor substrate 4 supports insulin- and interleukin 4-stimulated proliferation of hematopoietic cells.

Signaling from the activated insulin receptor is initiated by its tyrosine phosphorylation of the insulin receptor substrates (IRSs). The IRSs then act as docking/effector proteins for various signaling proteins containing src homology 2 domains. Four members of the IRS family, designated IRS-1 through IRS-4, have been identified. Although these IRSs show considerable structural homology, the extent to which they overlap in functions has not been explored in detail. The 32D hematopoietic cell line, which contains no detectable amounts of any IRS, provides a system in which to determine whether an IRS supports cell proliferation. Previous studies have shown that introduction of IRS-1 or -2 into 32D cells overexpressing the insulin and IL-4 receptors (32D-R cells) enables the cells to undergo mitogenesis in response to insulin and IL-4. In the present study, we have examined IRS-4, a member of the IRS family that we recently discovered, in this system. Expression of IRS-4 in 32D-R cells permitted the cells to undergo mitogenesis and continuous proliferation in response to insulin and IL-4. Immunoblotting of phosphotyrosine proteins showed that insulin and IL-4 elicited the tyrosine phosphorylation of IRS-4 in these cells. Thus, IRS-4, like IRS-1 and -2, can function in the signal transduction pathways linking insulin and IL-4 receptors to cell proliferation.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Mutation of tyrosine 960 within the insulin receptor juxtamembrane domain impairs glucose transport but does not inhibit ligand-mediated phosphorylation of insulin receptor substrate-2 in 3T3-L1 adipocytes.

CSF-1 is equipotent to insulin in its ability to stimulate 2-[3H]deoxyglucose uptake in 3T3-L1 adipocytes expressing the colony stimulating factor-1 receptor/insulin receptor chimera (CSF1R/IR). However, CSF-1-stimulated glucose uptake and glycogen synthesis is reduced by 50% in comparison to insulin in 3T3-L1 cells expressing a CSF1R/IR mutated at Tyr960 (CSF1R/IRA960). CSF-1-treated adipocytes expressing the CSF1R/IRA960 were impaired in their ability to phosphorylate insulin receptor substrate 1 (IRS-1) but not in their ability to phosphorylate IRS-2. Immunoprecipitation of IRS proteins followed by Western blotting revealed that the intact CSF1R/IR co-precipitates with IRS-2 from CSF-1-treated cells. In contrast, the CSF1R/IRA960 co-precipitates poorly with IRS-2. These observations suggest that Tyr960 is important for interaction of the insulin receptor cytoplasmic domain with IRS-2, but it is not essential to the ability of the insulin receptor tyrosine kinase to use IRS-2 as a substrate. These observations also suggest that in 3T3-L1 adipocytes, tyrosine phosphorylation of IRS-2 by the insulin receptor tyrosine kinase is not sufficient for maximal stimulation of receptor-regulated glucose transport or glycogen synthesis.

3T3 Cells↗

PubMed1999

IL-3 and IL-4 activate cyclic nucleotide phosphodiesterases 3 (PDE3) and 4 (PDE4) by different mechanisms in FDCP2 myeloid cells.

In FDCP2 myeloid cells, IL-4 activated cyclic nucleotide phosphodiesterases PDE3 and PDE4, whereas IL-3, granulocyte-macrophage CSF (GM-CSF), and phorbol ester (PMA) selectively activated PDE4. IL-4 (not IL-3 or GM-CSF) induced tyrosine phosphorylation of insulin-receptor substrate-2 (IRS-2) and its association with phosphatidylinositol 3-kinase (PI3-K). TNF-alpha, AG-490 (Janus kinase inhibitor), and wortmannin (PI3-K inhibitor) inhibited activation of PDE3 and PDE4 by IL-4. TNF-alpha also blocked IL-4-induced tyrosine phosphorylation of IRS-2, but not of STAT6. AG-490 and wortmannin, not TNF-alpha, inhibited activation of PDE4 by IL-3. These results suggested that IL-4-induced activation of PDE3 and PDE4 was downstream of IRS-2/PI3-K, not STAT6, and that inhibition of tyrosine phosphorylation of IRS molecules might be one mechnism whereby TNF-alpha could selectively regulate activities of cytokines that utilized IRS proteins as signal transducers. RO31-7549 (protein kinase C (PKC) inhibitor) inhibited activation of PDE4 by PMA. IL-4, IL-3, and GM-CSF activated mitogen-activated protein (MAP) kinase and protein kinase B via PI3-K signals; PMA activated only MAP kinase via PKC signals. The MAP kinase kinase (MEK-1) inhibitor PD98059 inhibited IL-4-, IL-3-, and PMA-induced activation of MAP kinase and PDE4, but not IL-4-induced activation of PDE3. In FDCP2 cells transfected with constitutively activated MEK, MAP kinase and PDE4, not PDE3, were activated. Thus, in FDCP2 cells, PDE4 can be activated by overlapping MAP kinase-dependent pathways involving PI3-K (IL-4, IL-3, GM-CSF) or PKC (PMA), but selective activation of PDE3 by IL-4 is MAP kinase independent (but perhaps IRS-2/PI3-K dependent).

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1999

cbl-b inhibits epidermal growth factor receptor signaling.

The role of cbl-b in signaling by the epidermal growth factor receptor (EGFR) was studied and compared with c-cbl. We demonstrate in vivo, that cbl-b, like c-cbl, is phosphorylated and recruited to the EGFR upon EGF stimulation and both cbl proteins can bind to the Grb2 adaptor protein. To investigate the functional role of cbl proteins in EGFR signaling, we transfected cbl-b or c-cbl into 32D cells overexpressing the EGFR (32D/EGFR). This cell line is absolutely dependent on exogenous IL-3 or EGF for sustained growth. 32D/EGFR cells overexpressing cbl-b showed markedly inhibited growth in EGF compared to c-cbl transfectants and vector controls. This growth inhibition by cbl-b was the result of a dramatic increase in the number of cells undergoing apoptosis. Consistent with this finding, cbl-b overexpression markedly decreased the amplitude and duration of AKT activation upon EGF stimulation compared to either vector controls or c-cbl overexpressing cells. In addition, the duration of EGF mediated MAP kinase and Jun kinase activation in cells overexpressing cbl-b is shortened. These data demonstrate that cbl-b inhibits EGF-induced cell growth and that cbl-b and c-cbl have distinct roles in EGF mediated signaling.

Animals↗

PubMed1999

Elderly use of the ED in an Asian metropolis.

To compare emergency department (ED) use by elderly patients (age 65 yrs or older) with that by younger adult patients (age 15-64 yrs), a prospective consecutive chart review study was conducted from August 1, 1995 through May 31, 1996 in eight designated hospitals in Taipei city (which has 2.6 million residents, 8.4% of whom are 65 yrs or older). Patient age, sex, mode of arrival, living status, triage category, advanced life support (ALS) eligibility, referral, confinement to bed, intensive care unit (ICU) admission, impression, trauma mechanism, and disposition were recorded and compared between the two groups. Of 27,765 adult emergency patients studied during the 10 months, 24% were elderly. The elderly were more likely to be ambulance cases, of high acuity and ALS eligibility, living alone, bed-ridden, and ICU cases (19.4% v 10.5%, 14.8% v 5.5%, 14.7% v 4.3%, 9.7% v 4.1%, 16% v 1.1%, and 4.0 v 1.1%, respectively). The three leading illnesses in the elderly were cerebral vascular accident (6.6%), cancer (5.6%), and cardiovascular disease (5.6%), and the two most common trauma mechanisms were trip (fall from the same level surface) (57.2%) and traffic accident (20.7%). Twenty-seven percent and 22.7% of elderly were disposed to admission and observation, respectively, compared with the 10.9% and 11.4% of the younger patients. Elderly patients have significantly different and more severe presentations to the ED compared with younger adults.

Adolescent↗

PubMed1999

Renal abscess: early diagnosis and treatment.

The purpose of this study was to identify initial clinical characteristics that can lead to early diagnosis of renal abscess in the emergency department and predict poor prognosis. A retrospective review of 88 renal abscess patients, from April 1979 through January 1996, was conducted. Patients were categorized into two groups. In group 1, renal abscess was diagnosed by an emergency physician, whereas in group 2 renal abscess was not diagnosed by an emergency physician. Clinical characteristics included demographic data, predisposing medical problems, duration of illness before diagnosis, time spent in hospital diagnosis, initial signs and symptoms, laboratory tests, and radiology studies that may have been useful in the early diagnostic regimes. Clinical factors were also analyzed for their value in predicting poor prognosis. The mean age of 88 patients with renal abscess was 59.8 years. The most common predisposing disorder was diabetes mellitus, followed by renal calculi and ureteral obstruction. The duration of diagnosis by emergency physicians was shorter for group 1 patients (1.2 +/- .4 v group 2, 2.8 +/- 2.9 days; P < .01) and the blood urea nitrogen level was higher in group 1 (55.7 +/- 42.2 mg/dL, v group 2, 33.5 +/- 33.5 mg/dL; P = .02). In the early diagnosis of renal abscess, emergency physicians should focus on patients who have predisposing disorders, ie, diabetes mellitus, renal stones, immunosuppression, longer duration of symptoms of urinary tract infection, and renal failure, who should promptly be investigated with ultrasound in the emergency department. The cure rate after treatment with routine antibiotics plus percutaneous drainage was 64%. This therapy is recommended for initial treatment. Poor prognosis is associated with elderly patients with lethargy and with elevation of the serum blood urea nitrogen level.

Abscess↗

PubMed1999

Effect of ploidy, recruitment, environmental factors, and tamoxifen treatment on the expression of sigma-2 receptors in proliferating and quiescent tumour cells.

Recently, we demonstrated that sigma-2 receptors may have the potential to be a biomarker of tumour cell proliferation (Mach et al (1997) Cancer Res 57: 156-161). If sigma-2 receptors were a biomarker of tumour cell proliferation, they would be amenable to detection by non-invasive imaging procedures, thus eliminating many of the problems associated with the flow cytometric measures of tumour cell proliferation presently used in the clinic. To be a good biomarker of tumour cell proliferation, the expression of sigma-2 receptors must be essentially independent of many of the biological, physiological, and/or environmental properties that are found in solid tumours. In the investigation reported here, the mouse mammary adenocarcinoma lines, 66 (diploid) and 67 (aneuploid), 9L rat brain tumour cells, and MCF-7 human breast tumour cells were used to study the extent and kinetics of expression of sigma-2 receptors in proliferative (P) and quiescent (Q) tumour cells as a function of species, cell type, ploidy, pH, nutrient depletion, metabolic state, recruitment from the Q-cell compartment to the P-cell compartment, and treatment with tamoxifen. In these experiments, the expression of sigma-2 receptors solely reflected the proliferative status of the tumour cells. None of the biological, physiological, or environmental properties that were investigated had a measurable effect on the expression of sigma-2 receptors in these model systems. Consequently, these data suggest that the proliferative status of tumours and normal tissues can be non-invasively assessed using radiolabelled ligands that selectively bind sigma-2 receptors.

Adenocarcinoma↗

PubMed1999

Inhibitory effects of huperzine B on cholinesterase activity in mice.

AIM: To determine the anticholinesterase properties of huperzine B (Hup B) and compare with tacrine in vitro and in vivo. METHODS: Spectrophotometry was used to determine ChE activity. RESULTS: Hup B showed much more selective inhibition to acetylcholinesterase (AChE) than tacrine. The IC50 ratios of Hup B and tacrine for butyrylcholinesterase (BuChE): AChE were 65.8 and 0.54, respectively. Hup B ig exhibited higher efficacy on the inhibition of brain AChE than that of tacrine. Tacrine was more effective in the inhibition of serum BuChE in mice with severe concomitant peripheral adverse effects than Hup B. A single ig dose of Hup B produced steady state of AChE inhibition in 4 h. CONCLUSION: Hup B exhibits higher selectivity and efficacy in the inhibition of AChE, and lower toxicity in mice than tacrine.

Acetylcholinesterase↗

PubMed1999

HLA linked with leprosy in southern China: HLA-linked resistance alleles to leprosy.

According to the World Health Organization recommended multidrug therapy (WHO/MDT), we have carried out this study to investigate the presence of HLA-linked susceptibility or resistance to leprosy in a southern Chinese population. Sixty-nine leprosy patients and 112 healthy controls participated in the study. HLA-DR2 subtypes, HLA-B and MHC Class I chain-related A (MICA) alleles were typed at the DNA level using the polymerase chain reaction-single strand conformation polymorphism method. The frequencies of HLA-DR2-DRB1 alleles did not show any significant differences between the patient and the control groups, suggesting that the disease susceptibility was not associated with the DR2 subtypes in this southern Chinese population. On the other hand, in the multibacillary (MB) patients significantly decreased allele frequencies of HLA-B46 (0.040 in MB patients vs 0.129 in controls) and MICA-A5 (0.200 vs 0.380) were observed compared with the healthy controls. The calculated relative risk (RR) for B46 was 0.28; for MICA-A5, 0.52. In addition, on haplotype analysis the frequency of the HLA-B46/MICA-A5 haplotype was significantly decreased in the MB patients compared to controls (0.060 vs 0.233, RR = 0.22, p < 0.01). These results suggest that an HLA-linked disease-resistant gene to MB leprosy in southern China is in strong linkage disequilibrium with the HLA-B46/MICA-A5 haplotype. In other words, the resistant gene may be located near the HLA-B/MICA region and not in the HLA-DR locus.

China↗

PubMed1999

Improving effects of huperzine A on spatial working memory in aged monkeys and young adult monkeys with experimental cognitive impairment.

Our previous studies demonstrated that huperzine A, a reversible and selective acetylcholinesterase inhibitor, exerts beneficial effects on memory deficits in various rodent models of amnesia. To extend the antiamnesic action of huperzine A to nonhuman primates, huperzine A was evaluated for its ability to reverse the deficits in spatial memory produced by scopolamine in young adult monkeys or those that are naturally occurring in aged monkeys using a delayed-response task. Scopolamine, a muscarinic receptor antagonist, dose dependently impaired performance with the highest dose (0.03 mg/kg, i.m.) producing a significant reduction in choice accuracy in young adult monkeys. The delayed performance changed from an average of 26.8/30 trials correct on saline control to an average of 20.2/30 trials correct after scopolamine administration. Huperzine A (0.01-0. 1 mg/kg, i.m.) significantly reversed deficits induced by scopolamine in young adult monkeys on a delayed-response task; performance after an optimal dose (0.1 mg/kg) averaged 25.0/30 correct. In four aged monkeys, huperzine A (0.001-0.01 mg/kg, i.m.) significantly increased choice accuracy from 20.5/30 on saline control to 25.2/30 at the optimal dose (0.001 mg/kg for two monkeys and 0.01 mg/kg for the other two monkeys). The beneficial effects of huperzine A on delayed-response performance were long lasting; monkeys remained improved for about 24 h after a single injection of huperzine A. This study extended the findings that huperzine A improves the mnemonic performance requiring working memory in monkeys, and suggests that huperzine A may be a promising agent for clinical therapy of cognitive impairments in patients with Alzheimer's disease.

Aging↗

PubMed1998

ErbB-4 ribozymes abolish neuregulin-induced mitogenesis.

The epidermal growth factor-like receptor tyrosine kinase (ErbB) family is frequently overexpressed in a variety of human carcinomas, including breast cancer. To assist in characterizing the role of ErbB-4 in breast cancer, we generated three specific hammerhead ribozymes targeted to the ErbB-4 mRNA. These ribozymes, Rz6, Rz21, and Rz29, efficiently catalyzed the specific cleavage of ErbB-4 message in a cell-free system. We demonstrated that the neuregulin-induced mitogenic effect was abolished in ribozyme Rz29- and Rz6-transfected 32D/ErbB-4 cells. Inhibition of mitogenesis was characterized by ribozyme-mediated down-regulation of ErbB-4 expression. In addition, we provide the first evidence that different threshold levels of ErbB-4 expression and activation correlate with different responses to neuregulin stimulation. High levels of ErbB-4 expression, phosphorylation, and homodimerization are necessary for neuregulin-stimulated, interleukin 3-independent cell proliferation in the 32D/E4 cells. In the case of Rz29-transfected 32D/E4 cells, low levels of ErbB-4 expression allowed neuregulin-induced phosphorylation but were insufficient to couple the activated receptor to cellular signaling. Furthermore, expression of the functional ErbB-4 ribozyme in T47D human breast carcinoma cells led to a down-regulation of endogenous ErbB-4 expression and a reduction of anchorage-independent colony formation. These studies support the use of ErbB-4 ribozymes to define the role of ErbB-4 receptors in human cancers.

Animals↗

PubMed1998

ErbB2 expression increases the spectrum and potency of ligand-mediated signal transduction through ErbB4.

Interleukin 3-dependent murine 32D cells do not detectably express members of the ErbB receptor family and do not proliferate in response to known ligands for these receptors. 32D transfectants were generated expressing human ErbB4 alone (32D.E4) or with ErbB2 (32D.E2/E4). Epidermal growth factor (EGF), neuregulin 1-beta (NRG1-beta), betacellulin (BTC), transforming growth factor-alpha (TGF-alpha), heparin binding-EGF (HB-EGF), and amphiregulin were analyzed for their ability to mediate mitogenesis in these transfectants. 32D.E4 responded mitogenically to NRG1-beta and BTC. Surprisingly, EGF also induced significant DNA synthesis and TGF-alpha was negligibly mitogenic on 32D.E4 cells, whereas HB-EGF and amphiregulin were inactive. Although coexpression of ErbB2 with ErbB4 in 32D.E2/E4 cells did not significantly alter DNA synthesis in response to NRG1-beta or BTC, it greatly enhanced mitogenesis elicited by EGF and TGF-alpha and unmasked the ability of HB-EGF to induce proliferation. EGF-related ligands that exhibited potent mitogenic activity on 32D.E2/E4 cells at low concentrations induced adherence, morphological alterations, and up-regulation of the Mac-1 integrin and FcgammaRII/III at higher concentrations. While 125I-EGF could be specifically crosslinked to both 32D.E4 and 32D.E2/E4 cells, its crosslinking capacity was greatly enhanced in the cotransfected cells. The ability of the various ligands to mediate proliferation and/or adhesion in the two transfectants correlated with their capacity to induce substrate tyrosine phosphorylation and to initiate and sustain activation of mitogen-activated protein kinase. We conclude that the ability of ErbB4 to mediate signal transduction through EGF-like ligands is broader than previously assumed and can be profoundly altered by the concomitant expression of ErbB2.

Amphiregulin↗

PubMed1998

Epiregulin is a potent pan-ErbB ligand that preferentially activates heterodimeric receptor complexes.

The ErbB signaling network consists of four transmembrane receptor tyrosine kinases and more than a dozen ligands sharing an epidermal growth factor (EGF) motif. The multiplicity of ErbB-specific ligands is incompletely understood in terms of signal specificity because all ErbB molecules signal through partially overlapping pathways. Here we addressed the action of epiregulin, a recently isolated ligand of ErbB-1. By employing a set of factor-dependent cell lines engineered to express individual ErbBs or their combinations, we found that epiregulin is the broadest specificity EGF-like ligand so far characterized: not only does it stimulate homodimers of both ErbB-1 and ErbB-4, it also activates all possible heterodimeric ErbB complexes. Consistent with its relaxed selectivity, epiregulin binds the various receptor combinations with an affinity that is approximately 100-fold lower than the affinity of ligands with more stringent selectivity, including EGF. Nevertheless, epiregulin's action upon most receptor combinations transmits a more potent mitogenic signal than does EGF. This remarkable discrepancy between binding affinity and bioactivity is permitted by a mechanism that prevents receptor down-regulation, and results in a weak, but prolonged, state of receptor activation.

Animals↗