Progesterone receptors - animal models and cell signaling in breast cancer: Role of steroid receptor coactivators and corepressors of progesterone receptors in breast cancer

Progesterone, an ovarian steroid hormone, plays a key role in the development and function of the mammary gland, as it also does in the uterus and the ovary. The action of progesterone is mediated through its intracellular cognate receptor, the progesterone receptor (PR), which functions as a transcription factor that regulates gene expression. As with other nuclear receptors, coregulators (coactivators and corepressors) recruited by the liganded or unliganded PR, either to enhance or to suppress transcription activity, modulate the function of the PR. Mutation or aberrant expression of the coregulators might thus affect the normal function of the PR and hence disrupt the normal development of the mammary gland, which may lead to breast cancer

E6-associated protein (E6-AP) is a dual function coactivator of steroid hormone receptors

Steroid hormone receptors (SHR) belong to a large family of ligand-activated transcription factors that perform their biological functions by enhancing the transcription of specific target genes. The transactivation functions of SHRs are regulated by a specialized group of proteins called coactivators. The SHR coactivators represent a growing class of proteins with various enzymatic activities that serve to modify the chromatin to facilitate the transcription of SHR target genes. The ubiquitin-proteasome pathway enzymes have also been added to the growing list of enzymatic activities that are recruited to the SHR target gene promoters during transcription. One such ubiquitin-proteasome pathway enzyme to be identified and characterized as a SHR coactivator was E6-associated protein (E6-AP). E6-AP is a hect (homologous to E6-associated protein carboxy-terminal domain) domain containing E3 ubiquitin ligase that possesses two independent separable functions; a coactivation function and an ubiquitin-protein ligase activity. Being a component of the ubiquitin-proteasome pathway, it is postulated that E6-AP may orchestrate the dynamics of steroid hormone receptor-mediated transcription by regulating the degradation of the transcriptional complexes. E6-AP has also been shown to be involved in the regulation of various aspects of reproduction such as prostate and mammary gland development. Furthermore, it has been demonstrated that E6-AP expression is down-regulated in breast and prostate tumors and that the expression of E6-AP is inversely associated with that of estrogen and androgen receptors. This review summarizes our current knowledge about the structures, molecular mechanisms, spatiotemporal expression patterns and biological functions of E6-AP

Digital-Literacy as the Predictor of Political-Participation a Survey of University Graduates in DIKhan, KP, Pakistan

This study examines the impact of digital literacy on student s participation in Political Activism The computer internet and cell phone has given rise to the interactive and participatory role of youth in active politics Survey approach was adopted for data collection Data was collected through Structured-Questionnaire constructed using the variables extracted from literature Questionnaire included 6 Demographic and 6 Research variables 4 Predictors and 2 Criterion expressed through 43 questions First hypothesis was examined through Correlation-Procedure 2nd and 3rd hypotheses were answered by using Regression-Analysis This study will be a role model guideline for researchers working in same line of issues It will provide a local version of the problem thereby helping to design and plan their research projects accordingl

Kangaroo mother care: Opportunities and implications for rural Pakistan

Neonatal mortality comprises 40% of total under-5 mortality, globally. Kangaroo mother care (KMC) is one of the most cost-effective interventions to reduce neonatal mortality. KMC does not require highend equipment, intensive care facilities or technical knowledge. A recent meta-analysis reported that KMC may reduce neonatal mortality in preterm and low birth weight neonates up to 36%. A review of enablers and barriers of KMC suggests that KMC can be integrated in maternal health care system by giving awareness, involving family and giving ownership of the intervention to the community. If supported with minimal incentives it would reduce the cost of health care substantially, reduce patient burden on hospitals by reducing hospital stay in postnatal period. It will reduce financial burden, time strain and help eliminate social taboos regarding preterm and low birth weight neonates. Hospital and community based KMC interventions should be tested in Pakistan

Molecular Mechanism of Action of Steroid Hormone Receptors

A novel bacterial expression system that is capable of producing high levels of soluble, stable, biologically active human vitamin D3 and estrogen receptors has been developed. The method utilizes ubiquitin fusion technology and a low temperature nalidixic acid induction of the lambda PL promoter. This system can produce large quantities of receptor antigen, but only a small fraction displays wild-type DNA and hormone binding properties. Therefore, the use of this system to overproduce receptors for crystallization studies is not practical. To overcome these problems, a 2 um based ubiquitin fusion system which allows regulated expression of the estrogen receptor in yeast (Saccharomyces cerevisiae) was developed. This system produces the estrogen receptor to a level of 0.2% of the total soluble protein. Moreover, this protein is undegradable, soluble, and biologically active. To test the transcriptional activity of the estrogen receptor produced in yeast, a cis-trans transcription assay was developed. This assay revealed that the transcriptional activity of the human estrogen receptor expressed in yeast was similar to that observed in transfected mammalian cells. This reconstituted estrogen transcription unit in Saccharomyces cerevisiae was utilized to examine the regulation of estrogen receptor functions by antiestrogens, to develop a random and rapid approach for identifying novel estrogen response elements, to characterize estrogen receptor variants cloned from human breast tumors, and to examine the effect of estrogen receptor on the regulation of osteocalcin gene

Effect of sorbic acid and some other food preservatives on human serum cholinesterase activity

The effect of some selected food preservatives on serum cholinesterase was determined. It was found that potassium metabisulphite, methyl parabene and propyl parabene caused a significant increase while sacharine, benzoic acid, salicylic acid, copper carbonate and sorbic acid caused a significant decrease in cholinesterase activity. The behavior of serum cholinesterase activity in response to a gradual change in the incubation time as well as the sorbic acid concentration was also studied. The graphical and statistical analysis of the data showed an exponential decrease in cholinesterase activity with an increase in the concentration of sorbic acid. The cholinesterase activity was also found to be decreased exponentially with an increase in the incubation time. The regression analysis showed a good agreement between the experimental and calculated values.Keywords: Sorbic acid, enzyme activity, cholinesterase, inhibition sensitivit

The roles of sex steroid receptor coregulators in cancer

Sex steroid hormones, estrogen, progesterone and androgen, play pivotal roles in sex differentiation and development, and in reproductive functions and sexual behavior. Studies have shown that sex steroid hormones are the key regulators in the development and progression of endocrine-related cancers, especially the cancers of the reproductive tissues. The actions of estrogen, progesterone and androgen are mediated through their cognate intracellular receptor proteins, the estrogen receptors (ER), the progesterone receptors (PR) and the androgen receptor (AR), respectively. These receptors are members of the nuclear receptor (NR) superfamily, which function as transcription factors that regulate their target gene expression. Proper functioning of these steroid receptors maintains the normal responsiveness of the target tissues to the stimulations of the steroid hormones. This permits the normal development and function of reproductive tissues. It can be inferred that factors influencing the expression or function of steroid receptors will interfere with the normal development and function of the target tissues, and may induce pathological conditions, including cancers. In addition to the direct contact with the basal transcription machinery, nuclear receptors enhance or suppress transcription by recruiting an array of coactivators and corepressors, collectively named coregulators. Therefore, the mutation or aberrant expression of sex steroid receptor coregulators will affect the normal function of the sex steroid receptors and hence may participate in the development and progression of the cancers

2012 Conference on Disarmament Pakistan's Approach towards FMCT

[While Conference on Disarmament (CD) has remained in a kind of deadlock over the years, any breakthrough during the 2012 session is also unlikely, owing to grave differences between the members - including on the agenda and work program. Important agenda items such as Disarmament and Prevention of Arms Race in Outer Space (PAROS) are getting lesser attention while issues such as Fissile Material Cut-Off Treaty (FMCT) are highlighted as blocking the progress of CD. It is being concluded that Pakistan is the only state, which could obstruct the 2012 CD Agenda, particularly FMCT, while the reports of international institutions including UNSG reveal that it is not the case. Pakistan's principled stance on FMCT is essential for its national security interests, as the country needs fissile materials for both its conventional and unconventional deterrence. The stance should be upheld and compromising it due to international pressures is not advisable.

Afghanistan: The Possible Arena for Major Powers Inevitable Cooperation

Afghanistan has been a center of a struggle between major powers since the 19th century. In 2001, the fight against terrorism had sparked a new power struggle among local, regional, and international Afghanistan actors. Various state and non-state players with conflicting perspectives and conflicting approaches are trying to pursue their strategic, political, and economic goals in Afghanistan. Due to similar security threats, complex economic interdependence, and economic liberalism, different scenarios may emerge in Afghanistan, leading to the potential collaboration of major global and regional powers in Afghanistan. This partnership can be expanded for several logics and reasons, among which security comes first. The peace treaty concluded between the United States and the Taliban on February 29, 2020. The continuing peace process via intra-Afghan peace talks with regional states has fortified hopes for peace in Afghanistan through cooperative measures among major regional and international powers