21 research outputs found
P53 and p73 differ in their ability to inhibit glucocorticoid receptor (GR) transcriptional activity
BACKGROUND: p53 is a tumor suppressor and potent inhibitor of cell growth. P73 is highly similar to p53 at both the amino acid sequence and structural levels. Given their similarities, it is important to determine whether p53 and p73 function in similar or distinct pathways. There is abundant evidence for negative cross-talk between glucocorticoid receptor (GR) and p53. Neither physical nor functional interactions between GR and p73 have been reported. In this study, we examined the ability of p53 and p73 to interact with and inhibit GR transcriptional activity. RESULTS: We show that both p53 and p73 can bind GR, and that p53 and p73-mediated transcriptional activity is inhibited by GR co-expression. Wild-type p53 efficiently inhibited GR transcriptional activity in cells expressing both proteins. Surprisingly, however, p73 was either unable to efficiently inhibit GR, or increased GR activity slightly. To examine the basis for this difference, a series of p53:p73 chimeric proteins were generated in which corresponding regions of either protein have been swapped. Replacing N- and C-terminal sequences in p53 with the corresponding sequences from p73 prevented it from inhibiting GR. In contrast, replacing p73 N- and C-terminal sequences with the corresponding sequences from p53 allowed it to efficiently inhibit GR. Differences in GR inhibition were not related to differences in transcriptional activity of the p53:p73 chimeras or their ability to bind GR. CONCLUSION: Our results indicate that both N- and C-terminal regions of p53 and p73 contribute to their regulation of GR. The differential ability of p53 and p73 to inhibit GR is due, in part, to differences in their N-terminal and C-terminal sequences
Self-optimization wavelet-learning method for predicting nonlinear thermal conductivity of highly heterogeneous materials with randomly hierarchical configurations
In the present work, we propose a self-optimization wavelet-learning method
(SO-W-LM) with high accuracy and efficiency to compute the equivalent nonlinear
thermal conductivity of highly heterogeneous materials with randomly
hierarchical configurations. The randomly structural heterogeneity,
temperature-dependent nonlinearity and material property uncertainty of
heterogeneous materials are considered within the proposed self-optimization
wavelet-learning framework. Firstly, meso- and micro-structural modeling of
random heterogeneous materials are achieved by the proposed computer
representation method, whose simulated hierarchical configurations have
relatively high volume ratio of material inclusions. Moreover,
temperature-dependent nonlinearity and material property uncertainties of
random heterogeneous materials are modeled by a polynomial nonlinear model and
Weibull probabilistic model, which can closely resemble actual material
properties of heterogeneous materials. Secondly, an innovative stochastic
three-scale homogenized method (STSHM) is developed to compute the macroscopic
nonlinear thermal conductivity of random heterogeneous materials. Background
meshing and filling techniques are devised to extract geometry and material
features of random heterogeneous materials for establishing material databases.
Thirdly, high-dimensional and highly nonlinear material features of material
databases are preprocessed and reduced by wavelet decomposition technique. The
neural networks are further employed to excavate the predictive models from
dimension-reduced low-dimensional data
Higher-order multi-scale deep Ritz method for multi-scale problems of authentic composite materials
The direct deep learning simulation for multi-scale problems remains a
challenging issue. In this work, a novel higher-order multi-scale deep Ritz
method (HOMS-DRM) is developed for thermal transfer equation of authentic
composite materials with highly oscillatory and discontinuous coefficients. In
this novel HOMS-DRM, higher-order multi-scale analysis and modeling are first
employed to overcome limitations of prohibitive computation and Frequency
Principle when direct deep learning simulation. Then, improved deep Ritz method
are designed to high-accuracy and mesh-free simulation for macroscopic
homogenized equation without multi-scale property and microscopic lower-order
and higher-order cell problems with highly discontinuous coefficients.
Moreover, the theoretical convergence of the proposed HOMS-DRM is rigorously
demonstrated under appropriate assumptions. Finally, extensive numerical
experiments are presented to show the computational accuracy of the proposed
HOMS-DRM. This study offers a robust and high-accuracy multi-scale deep
learning framework that enables the effective simulation and analysis of
multi-scale problems of authentic composite materials
RecQL4 helicase amplification is involved in human breast tumorigenesis.
Breast cancer occur both in hereditary and sporadic forms, and the later one comprises an overwhelming majority of breast cancer cases among women. Numerical and structural alterations involving chromosome 8, with loss of short arm (8p) and gain of long arm (8q), are frequently observed in breast cancer cells and tissues. In this study, we show that most of the human breast tumor cell lines examined display an over representation of 8q24, a chromosomal locus RecQL4 is regionally mapped to, and consequently, a markedly elevated level of RecQL4 expression. An increased RecQL4 mRNA level was also observed in a majority of clinical breast tumor samples (38/43) examined. shRNA-mediated RecQL4 suppression in MDA-MB453 breast cancer cells not only significantly inhibit the in vitro clonogenic survival and in vivo tumorigenicity. Further studies demonstrate that RecQL4 physically interacts with a major survival factor-survivin and its protein level affects survivin expression. Although loss of RecQL4 function due to gene mutations causally linked to occurrence of human RTS with features of premature aging and cancer predisposition, our studies provide the evidence that overexpression of RecQL4 due to gene amplification play a critical role in human breast tumor progression