RESUMEN

HLJ1 (DNAJB4), a DNAJ/Hsp40 chaperone, has emerged as a novel prognostic marker in lung cancers; however, the molecular contribution and functionality in neoplastic diseases remain to be established. This study demonstrated that HLJ1 inhibits epithelial-mesenchymal transition in vitro and reduces lung cancer metastasis in vivo. Using shRNA silencing and ectopic expression of HLJ1, we found that HLJ1 not only suppresses catalytic activity of Src but also downregulates the formation of oncogenic complexes associated with the EGFR, FAK and STAT3 signaling pathways. A screen of specimens from HLJ1-knockout mice and lung cancer patients validated that HLJ1 expression is inversely correlated with Src activity. Mechanistically, HLJ1 protein directly bound to catalytic and protein-binding domains of Src through its amino acid Y172 and the P301/P304 motif. Following Src-induced HLJ1 phosphorylation at Y172, HLJ1-Src interaction was elevated, resulting in Src inhibition and malignancy suppression. Interestingly, both Src-binding regions also occurred in other DNAJB family members and contributed to anti-invasive activities of DNAJB proteins. We conclude that HLJ1 is an endogenous Src inhibitor that can suppress cancer metastasis through complex interacting mechanisms. This HLJ1-Src complex might provide a promising molecular model for developing new anticancer strategies.

Asunto(s)

Proteínas del Choque Térmico HSP40/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Familia-src Quinasas/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Activación Enzimática , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Proteínas del Choque Térmico HSP40/química , Proteínas del Choque Térmico HSP40/genética , Proteínas del Choque Térmico HSP40/farmacología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Noqueados , Modelos Biológicos , Modelos Moleculares , Mutación , Invasividad Neoplásica , Metástasis de la Neoplasia , Neoplasias/genética , Unión Proteica , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , Interferencia de ARN , ARN Interferente Pequeño/genética , Dominios Homologos src , Familia-src Quinasas/química , Familia-src Quinasas/metabolismo

RESUMEN

The tumor-suppressor gene p53 acts as "the guardian of the genome", sensing DNA damage and initiating protective responses. To examine the hypothesis that p53 abnormality leads to increased genomic alterations in primary tumor cells, our study utilized 51 primary tumors of cervical carcinoma and 10 microsatellite markers. These markers were mapped to the short arms of chromosomes 3 and 5, covering the regions 3p13-25 and 5p15.1-15.3. Genomic deletion on 3p and 5p was correlated with genetic or epigenetic p53 inactivation pathways, including p53 mutation, genetic deletion of p53 and cervical infection with human papillomavirus. The proportion of abnormal p53 was found to be significantly higher in the cases exhibiting loss of heterozygosity (LOH) on 5p (p < 0.001), supporting the hypothesis of the presence of a p53-dependent pathway to cervical tumorigenesis. In contrast, however, LOH on 3p was found to be independent of p53 inactivation. A common deletion region, 3p22-24, was identified in 44% of informative cases, and genomic loss at this specific region was correlated with early tumorigenic onset and poor grade of tumor differentiation. Diversity within the patterns of genomic alteration in the same form of cancer suggests different sets of risk/tumorigenic profiles, molecular pathogenesis, as well as prognosis and outcome.

Asunto(s)

Carcinoma/genética , Cromosomas Humanos Par 3 , Cromosomas Humanos Par 5 , Eliminación de Gen , Genoma Humano , Proteína p53 Supresora de Tumor/genética , Neoplasias del Cuello Uterino/genética , Adulto , Anciano , Mapeo Cromosómico , Femenino , Humanos , Persona de Mediana Edad

RESUMEN

Two-dimensional (2-D) adaptive filtering is a technique that can be applied to many image processing applications. This paper will focus on the development of an improved 2-D adaptive lattice algorithm (2-D AL) and its application to the removal of correlated clutter to enhance the detectability of small objects in images. The two improvements proposed here are increased flexibility in the calculation of the reflection coefficients and a 2-D method to update the correlations used in the 2-D AL algorithm. The 2-D AL algorithm is shown to predict correlated clutter in image data and the resulting filter is compared with an ideal Wiener-Hopf filter. The results of the clutter removal will be compared to previously published ones for a 2-D least mean square (LMS) algorithm. 2-D AL is better able to predict spatially varying clutter than the 2-D LMS algorithm, since it converges faster to new image properties. Examples of these improvements are shown for a spatially varying 2-D sinusoid in white noise and simulated clouds. The 2-D LMS and 2-D AL algorithms are also shown to enhance a mammogram image for the detection of small microcalcifications and stellate lesions.

RESUMEN

This work studies the performance of dimensional least mean square (TDLMS) adaptive filters as prewhitening filters for the detection of small objects in image data. The object of interest is assumed to have a very small spatial spread and is obscured by correlated clutter of much larger spatial extent. The correlated clutter is predicted and subtracted from the input signal, leaving components of the spatially small signal in the residual output. The receiver operating characteristics of a detection system augmented by a TDLMS prewhitening filter are plotted using Monte-Carlo techniques. It is shown that such a detector has better operating characteristics than a conventional matched filter in the presence of correlated clutter. For very low signal-to-background ratios, TDLMS-based detection systems show a considerable reduction in the number of false alarms. The output energy in both the residual and prediction channels of such filters is shown to be dependent on the correlation length of the various components in the input signal. False alarm reduction and detection gains obtained by using this detection scheme on thermal infrared sensor data with known object positions is presented.

RESUMEN

X-ray astronomy has reached sufficient maturity to demand at least moderate angular resolution lightgathering telescopes to accompany detector development. Keeping the cost of such telescopes within the budget of low-cost flight opportunities such as sounding rockets and SPARTAN missions is a substantial challenge. We have developed a program of precision diamond mirror turning, mechanical polishing, lacquer coating, and metal deposition which produces x-ray telescopes with minute of arc angular resolution at moderate cost. We describe the process and report calibration results for a 80 cm (31.4 in.) diam Wolter I telescope flown aboard an Aries sounding rocket.

RESUMEN

Observations of the Trapezium region in the Orion Nebula obtained with the high-resolution x-ray imaging instrument on board the Einstein Observatory reveal at least 58 sources of x-ray emission. All but two of the sources can be identified with visible stars. The strongest x-ray source is the star Theta(1)C, which excites the emission nebula. Its x-ray luminosity is 6 x 10(32) ergs per second. The rest of the x-ray sources may be identified with stars of all spectral types. Strong x-ray emission is not observed from members of the infrared cluster embedded within the Orion molecular cloud.