Long noncoding RNAs in prostate cancer: overview and clinical implications.

Prostate cancer is the second most common cause of cancer mortality among men in the United States. While many prostate cancers are indolent, an important subset of patients experiences disease recurrence after conventional therapy and progresses to castration-resistant prostate cancer (CRPC), which is currently incurable. Thus, there is a critical need to identify biomarkers that will distinguish indolent from aggressive disease, as well as novel therapeutic targets for the prevention or treatment of CRPC. In recent years, long noncoding RNAs (lncRNAs) have emerged as an important class of biological molecules. LncRNAs are polyadenylated RNA species that share many similarities with protein-coding genes despite the fact that they are noncoding (not translated into proteins). They are usually transcribed by RNA polymerase II and exhibit the same epigenetic signatures as protein-coding genes. LncRNAs have also been implicated in the development and progression of variety of cancers, including prostate cancer. While a large number of lncRNAs exhibit tissue- and cancer-specific expression, their utility as diagnostic and prognostic biomarkers is just starting to be explored. In this review, we highlight recent findings on the functional role and molecular mechanisms of lncRNAs in the progression of prostate cancer and evaluate their use as potential biomarkers and therapeutic targets

A study on Impact of Job Characteristics on Key Attitudes of Faculty Members in Professional Educational Institutes.

The purpose of the study was to investigate the impact of job characteristics on key attitudes (job satisfaction and organisational commitment) of faculty member’s in professional educational institutes in Delhi region. Also the study explored the satisfaction level and commitment level of faculty with different dimensions of their job. A survey  of 251 faculty members working in private professional educational institutes was conducted. Several analytical techniques were used such as Pearson correlation, Hierarchical regression to evaluate the relationship among variables. The findings of the study indicated that job characteristics promotional opportunities, task variety, pay satisfaction and professional development resulted into high affective commitment while participation in decision making was related with normative commitment. Promotional opportunity, pay and participation were highly related with job satisfaction of the faculty members

A STUDY ON THE IMPACT OF JOB CHARACTERISTICS ON KEY ATTITUDES OF FACULTY MEMBERS IN PROFESSIONAL EDUCATIONAL INSTITUTES

The purpose of this study is to investigate the impact of job characteristics on key attitudes (job satisfaction and organizational commitment) of faculty members in professional educational institutes in Delhi region. In addition, the study explored the satisfaction level and commitment level of faculty members with different dimensions of their job. A survey of 251 faculty members working in private professional educational institutes was conducted. Several analytical techniques such as Pearson correlation and Hierarchical regression were used to evaluate the relationship among variables. The findings of the study indicated that job characteristics promotional opportunities, task variety, pay satisfaction, and professional development, resulted in a high affective commitment, while participation in decision making was related to normative commitment. Promotional opportunity, pay, and participation were highly related with the job satisfaction of the faculty members

A STUDY ON THE IMPACT OF JOB CHARACTERISTICS ON KEY ATTITUDES OF FACULTY MEMBERS IN PROFESSIONAL EDUCATIONAL INSTITUTES

The purpose of this study is to investigate the impact of job characteristics on key attitudes (job satisfaction and organizational commitment) of faculty members in professional educational institutes in Delhi region. In addition, the study explored the satisfaction level and commitment level of faculty members with different dimensions of their job. A survey of 251 faculty members working in private professional educational institutes was conducted. Several analytical techniques such as Pearson correlation and Hierarchical regression were used to evaluate the relationship among variables. The findings of the study indicated that job characteristics promotional opportunities, task variety, pay satisfaction, and professional development, resulted in a high affective commitment, while participation in decision making was related to normative commitment. Promotional opportunity, pay, and participation were highly related with the job satisfaction of the faculty members

Significance of Protein Interactions in Mediating AF9 Function

Rearrangements of the MLL gene at chromosome band 11q23 have been associated with a heterogeneous group of lymphoid, myeloid and mixed lineage leukemias. MLL rearrangements occur approximately in 70% of infant leukemias and are also common in therapy-related leukemias where patients were previously treated with topoisomerase II inhibitors. Unfortunately, these patients have a poor prognosis. MLL gene rearrangements give rise to chimeric proteins that contain the N-terminal portion of MLL fused to the C-terminal portion of over 50 different fusion partners. The chimeric proteins cause constitutive expression of some MLL target genes such as HOXA9 and MEIS1, and enhanced proliferation of hematopoietic progenitors. MLL chimeras do not retain the histone methyltransferase activity of wild type MLL and it is unclear how they deregulate the expression of MLL target genes. AF9 is one of the most common MLL fusion partners encountered in patients with leukemias. Moreover, Af9 is known to negatively regulate the expression of the epithelial sodium channel α (ENaCα) gene in murine renal collecting ducts by modulating the activity of the Dot1l. It has been shown that Af9-Dot1l promotes H3K79 methylation at specific sites in the ENaCα promoter, which then contributes to its repressed state. A number of reports have described the direct or indirect association of the C-terminus of AF9 with several distinct proteins including activators as well as repressors of transcription apart from DOT1L. Our data indicate that other AF9 binding proteins compete with DOT1L thereby diminishing its activity. Specifically, we show that AF9 is part of a protein multimer containing members of Polycomb group PRC1 complex, CBX8, RING1B, and BMI1. The interaction of AF9 with other PRC1 proteins is directly mediated by CBX8 and precludes AF9-DOT1L binding. Knockdown of CBX8 with shRNA leads to decreased ENaCα mRNA levels. In contrast, CBX8 overexpression results in increased ENaCα mRNA levels and this effect can be partially overcome by co-overexpression of AF9. As predicted, expression of CBX8 is accompanied by decreased H3K79 trimethylation at ENaCα promoter regions. Thus, our data suggest that changing the abundance of different AF9 binding partners shifts the equilibrium of functionally distinct AF9 complexes and alters the regulation of target genes. Moreover, although CBX8 is part of the repressive PRC1 Polycomb complex, its increased expression may actually increase the expression of genes normally repressed by DOT1L through its interaction with AF9. Furthermore, it has been shown that AF4 and AF9 exist in a large multiprotein complex containing positive transcription elongation factor b (P-TEFb) and therefore are linked to transcriptional elongation. To understand the significance of the AF9-AF4 interaction, our laboratory has mapped the domains involved in their binding and has developed synthetic peptides (PFWT and SPK-111) capable of disrupting their interaction in vitro and in vivo. The peptides mimic the amino acid sequence of the AF9 binding domain within AF4. These peptides are toxic to MLL-AF4 and MLL-AF9 fusion harboring leukemic cell lines, suggesting the importance of the AF9-AF4 interaction for the survival of these leukemic cells. However, the molecular mechanism of action of peptide is still not known. We showed that after peptide treatment, MV4-11 (MLL-AF4) and MOLM13 (MLL-AF9) leukemic cells have reduced levels of MEIS1 and MYC expression both at the transcript levels and protein levels. MEIS1 and c-MYC are known targets of MLL fusion proteins. Moreover, the reduced MYC transcript levels correlate with the decreased recruitment of cyclin dependent kinase 9 (CDK9), a component of P-TEFb and phosphorylation of Ser2 of C-terminal domain (CTD) of RNA PolII. Hence, our data suggest that peptide mediated disruption of AF9-AF4 interaction interferes with the stable complex formation involving P-TEFb, which further impairs the productive elongation of the transcripts. Therefore, modulation of protein-protein interactions involving AF9 would be predicted to have important effects on disease processes that subvert AF9, including MLL-AF9 leukemias

Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo

Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification

Long noncoding RNAs in prostate cancer: overview and clinical implications.

Prostate cancer is the second most common cause of cancer mortality among men in the United States. While many prostate cancers are indolent, an important subset of patients experiences disease recurrence after conventional therapy and progresses to castration-resistant prostate cancer (CRPC), which is currently incurable. Thus, there is a critical need to identify biomarkers that will distinguish indolent from aggressive disease, as well as novel therapeutic targets for the prevention or treatment of CRPC. In recent years, long noncoding RNAs (lncRNAs) have emerged as an important class of biological molecules. LncRNAs are polyadenylated RNA species that share many similarities with protein-coding genes despite the fact that they are noncoding (not translated into proteins). They are usually transcribed by RNA polymerase II and exhibit the same epigenetic signatures as protein-coding genes. LncRNAs have also been implicated in the development and progression of variety of cancers, including prostate cancer. While a large number of lncRNAs exhibit tissue- and cancer-specific expression, their utility as diagnostic and prognostic biomarkers is just starting to be explored. In this review, we highlight recent findings on the functional role and molecular mechanisms of lncRNAs in the progression of prostate cancer and evaluate their use as potential biomarkers and therapeutic targets

CBX8, a component of the Polycomb PRC1 complex, modulates DOT1L-mediated gene expression through AF9/MLLT3

AbstractAF9 is known to interact with multiple proteins including activators and repressors of transcription. Our data indicate that other AF9 binding proteins compete with the histone methyltransferase DOT1L for AF9 binding thus diminishing its ability to methylate lysine 79 of histone 3. Specifically, we show that AF9 is part of a protein multimer containing members of Polycomb group (PcG) PRC1 complex, CBX8, RING1B, and BMI1. Interaction with CBX8 precludes AF9–DOT1L binding. Knockdown of CBX8 with short-hairpin RNA (shRNA) leads to decreased expression of the AF9 target gene ENaCα. In contrast, CBX8 overexpression results in increased ENaCα mRNA levels and this effect can be partially overcome by co-overexpression of AF9