The Prolyl Isomerase Pin1 Acts Synergistically with CDK2 to Regulate the Basal Activity of Estrogen Receptor α in Breast Cancer

In hormone receptor-positive breast cancers, most tumors in the early stages of development depend on the activity of the estrogen receptor and its ligand, estradiol. Anti-estrogens, such as tamoxifen, have been used as the first line of therapy for over three decades due to the fact that they elicit cell cycle arrest. Unfortunately, after an initial period, most cells become resistant to hormonal therapy. Peptidylprolyl isomerase 1 (Pin1), a protein overexpressed in many tumor types including breast, has been demonstrated to modulate ERalpha activity and is involved in resistance to hormonal therapy. Here we show a new mechanism through which CDK2 drives an ERalpha-Pin1 interaction under hormone- and growth factor-free conditions. The PI3K/AKT pathway is necessary to activate CDK2, which phosphorylates ERalphaSer294, and mediates the binding between Pin1 and ERalpha. Site-directed mutagenesis demonstrated that ERalphaSer294 is essential for Pin1-ERalpha interaction and modulates ERalpha phosphorylation on Ser118 and Ser167, dimerization and activity. These results open up new drug treatment opportunities for breast cancer patients who are resistant to anti-estrogen therapy. © 2013 Lucchetti et al

Coordinated interaction of multifunctional members of the p53 family determines many key processes in multicellular organisms

For the first time, p53 was found in complex with the viral large T-antigen in cells transformed with the small DNA virus SV40. p53 cDNA was cloned in the early 1980s, and the full-length p53 gene was cloned soon afterwards. The p53 family is comprised of three genes—TP53, TP63, and TP73—each of which is expressed as a set of structurally and functionally different isoforms. All of them intensely interact with each other, forming a united functional network of proteins. The review discusses the evolution of the p53 family and the significance of all its members in embryo development, reproduction, regeneration, regulation of aging and lifespan, and defense against cancer. Special attention is paid to the role of poorly studied members of the p53 family, p63 and p73, in carcinogenesis and tumor progression. Different isoforms of these proteins might exert opposite effects on these processes

Method for Monitoring of Managing the Modernization of Regional Economy

This paper proposes a new approach for monitoring of managing the modernisation of regional economic. The model built on proposed methodology will make it possible to smooth out the influence of non-urban areas on the unevenness of economic activity in spatial development. This paper has two goals. The first is to provide a new compilation of data on spatial distribution of economic activity at the sub-regional level. This data set allows us to monitoring of different indicators within macroregions such as Siberia. The second goal is to construct an instrument that helps to overcome the endogeneity problem using new economic geography hypothesis about the mechanisms of distribution of economic activity. Section 2 describes the data and method that we have proposed, discusses the construction of the Theil indexes using these data at the sub-federal and the sub-regional level. Section 3 presents the correlations between spatial distribution of economic activity and local market potential, discusses the robustness of the results; and the last section concludes

Characterization of ΔNp73 expression and regulation in gastric and esophageal tumors

p73 is a member of the p53 protein family. Although the tumor suppressor function of p53 is clearly defined, the role of p73 in tumorigenesis is still a matter of debate. A complex pattern of expression of p73 isoforms makes it difficult to unambiguously interpret the experimental results. Previously, we and others have found that the N-terminally truncated isoform of p73, ΔNp73, has potent anti-apoptotic and oncogenic properties in vitro and in vivo. In the present study, we analyzed, for the first time, the regulation of ΔNp73 in a large number of gastric, gastroesophageal junction and esophageal tumors. We found that expression of ΔNp73 mRNA and protein is increased in these neoplasms. Furthermore, the up-regulation of the ΔNp73 protein is significantly associated with poor patient survival. Oncogenic properties of ΔNp73 were further confirmed by finding that ΔNp73 facilitates anchorage-independent growth of gastric epithelial cells in soft agar. As little is currently known about the regulation of ΔNp73 transcription, we investigated the alternative p73 gene promoter that mediates the ΔNp73 expression. Analyzing the ΔNp73 promoter in silico as well as by using chromatin immunoprecipitation, site-directed mutagenesis and deletion analyses we identified the evolutionary conserved region within the ΔNp73 promoter that contains binding sites for HIC1 protein. We found that HIC1 negatively regulates ΔNp73 transcription in mucosal epithelial cells. This leads to a decrease in ΔNp73 protein levels and may normally control the oncogenic potential of the ΔNp73 isoform