Elimination of Proliferating Cells Unmasks the Shift from Senescence to Quiescence Caused by Rapamycin

Background: Depending on cellular context, p53-inducing agents (such as nutlin-3a) cause different outcomes including reversible quiescence and irreversible senescence. Inhibition of mTOR shifts the balance from senescence to quiescence. In cell lines with incomplete responses to p53, this shift may be difficult to document because of a high proportion of proliferating cells contaminating arrested (quiescent and senescent) cells. This problem also complicates the study of senescence caused by minimal levels of p21 that are capable to arrest a few cells. Methodology: During induction of senescence by low levels of endogenous p53 and ectopic p21, cells were co-treated with nocodazole, which eliminated proliferating cells. As a result, only senescent and quiescent cells remained. Results and Discussion: This approach revealed that rapamycin efficiently converted nutlin-induced-senescence into quiescence. In the presence of rapamycin, nutlin-arrested MCF-7 cells retained the proliferative potential and small/lean morphology. Using this approach, we also unmasked senescence in cells arrested by low levels of ectopic p21, capable to arrest only a small proportion of HT1080-p21-9 cells. When p21 did cause arrest, mTOR caused senescent phenotype. Rapamycin and high concentrations of nutlin-3a, which inhibit the mTOR pathway in these particular cells, suppressed senescence, ensuring quiescence instead. Thus, p21 causes senescence passively, just by causing arrest, while still activ

МЕХАНИЗМ ТРАНСФОРМАЦИИ ОРГАНИЗАЦИОННОЙ КУЛЬТУРЫ В ИННОВАЦИОННЫЕ КОНКУРЕНТНЫЕ ПРЕИМУЩЕСТВА МЕЖДУНАРОДНЫХ ПРЕДПРИНИМАТЕЛЬСКИХ СТРУКТУР

The article presents mechanisms of organizational culture formation and development in the conditions of cross-cultural interaction on the example of the international enterprise structures - Hyundai Motor Corporation group of companies and its affiliated structures are considered: «Hyundai Glovis» and Russian company «Hyundai Glovis Russia». The Russian and Korean cultural aspects of business and daily communication feature of mentality of two cultures, the priority directions of development of organizational culture based on cross-cultural interaction are analyzed for this purpose.В настоящей статье рассматриваются механизмы формирования и развития организационной культуры в условиях кросс-культурного взаимодействия на примере международных предпринимательских структур - группы компаний «Hyundai Motor Corporation» и ее дочерних структур: «Hyundai Glovis» и российской компании «Hyundai Glovis Russia». В этих целях анализируются российские и корейские культурные аспекты деловой и повседневной коммуникации, особенности менталитета двух культур, приоритетные направления развития организационной культуры на основе кросс-культурного взаимодействия

МЕХАНИЗМ ТРАНСФОРМАЦИИ ОРГАНИЗАЦИОННОЙ КУЛЬТУРЫ В ИННОВАЦИОННЫЕ КОНКУРЕНТНЫЕ ПРЕИМУЩЕСТВА МЕЖДУНАРОДНЫХ ПРЕДПРИНИМАТЕЛЬСКИХ СТРУКТУР

Throughout article authors give algorithm of organizational culture diagnostic testing of the Hyundai Glovis Russia company, features and difficulties of her cross-cultural environment. Within research the corporate culture and history of the Hyundai Glovis Russia company is analysed. Besides, systems of norms, values and behavior models of the Korean and Russian personnel, and also set of forms of interaction between them are compared. The structural model of transformation of cultural distinctions in competitive advantages of the international enterprise structures is developed.В продолжении статьи авторами приводится алгоритм диагностического исследования организационной культуры компании «Hyundai Glovis Russia», особенностей и сложностей ее межкультурной среды. В рамках исследования проанализирована организационная культура и история компании «Hyundai Glovis Russia». Кроме того, сопоставлены системы норм, ценностей и моделей поведения корейского и российского персонала, а также совокупность форм взаимодействия между ними. Разработана структурная модель трансформации культурных различий в конкурентные преимущества международных предпринимательских структур

PKCα tumor suppression in the intestine is associated with transcriptional and translational inhibition of cyclin D1

Alterations in PKC isozyme expression and aberrant induction of cyclin D1 are early events in intestinal tumorigenesis. Previous studies have identified cyclin D1 as a major target in the antiproliferative effects of PKCα in non-transformed intestinal cells; however, a link between PKC signaling and cyclin D1 in colon cancer remained to be established. The current study further characterized PKC isozyme expression in intestinal neoplasms and explored the consequences of restoring PKCα or PKCδ in a panel of colon carcinoma cell lines. Consistent with patterns of PKC expression in primary tumors, PKCα and δ levels were generally reduced in colon carcinoma cell lines, PKCβII was elevated and PKCε showed variable expression, thus establishing the suitability of these models for analysis of PKC signaling. While colon cancer cells were insensitive to the effects of PKC agonists on cyclin D1 levels, restoration of PKCα downregulated cyclin D1 by two independent mechanisms. PKCα expression consistently (a) reduced steady-state levels of cyclin D1 by a novel transcriptional mechanism not previously seen in non-transformed cells, and (b) re-established the ability of PKC agonists to activate the translational repressor 4E-BP1 and inhibit cyclin D1 translation. In contrast, PKCδ had modest and variable effects on cyclin D1 steady state levels and failed to restore responsiveness to PKC agonists. Notably, PKCα expression blocked anchorage-independent growth in colon cancer cells via a mechanism partially dependent on cyclin D1 deficiency, while PKCδ had only minor effects. Loss of PKCα and effects of its re-expression were independent of the status of the APC/β-catenin signaling pathway or known genetic alterations, indicating that they are a general characteristic of colon tumors. Thus, PKCα is a potent negative regulator of cyclin D1 expression and anchorage-independent cell growth in colon tumor cells, findings that offer important perspectives on the frequent loss of this isozyme during intestinal carcinogenesis

Androgen Receptor Drives Cellular Senescence

The accepted androgen receptor (AR) role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS) and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor