Open Access. Powered by Scholars. Published by Universities.®
Articles 1 - 7 of 7
Full-Text Articles in Medicine and Health Sciences
Endogenous Cyclin D1 Promotes The Rate Of Onset And Magnitude Of Mitogenic Signaling Via Akt1 Ser473 Phosphorylation., Ke Chen, Xuanmao Jiao, Agnese Di Rocco, Duanwen Shen, Shaohua Xu, Adam Ertel, Zuoren Yu, Gabriele Di Sante, Min Wang, Zhiping Li, Timothy G Pestell, Mathew C Casimiro, Emmanuel Skordalakes, Samuel Achilefu, Richard G Pestell
Endogenous Cyclin D1 Promotes The Rate Of Onset And Magnitude Of Mitogenic Signaling Via Akt1 Ser473 Phosphorylation., Ke Chen, Xuanmao Jiao, Agnese Di Rocco, Duanwen Shen, Shaohua Xu, Adam Ertel, Zuoren Yu, Gabriele Di Sante, Min Wang, Zhiping Li, Timothy G Pestell, Mathew C Casimiro, Emmanuel Skordalakes, Samuel Achilefu, Richard G Pestell
Department of Cancer Biology Faculty Papers
Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates RB and functions as a collaborative nuclear oncogene. The serine threonine kinase Akt plays a pivotal role in the control of cellular metabolism, survival, and mitogenic signaling. Herein, Akt1-mediated phosphorylation of downstream substrates in the mammary gland is reduced by cyclin D1 genetic deletion and is induced by mammary-gland-targeted cyclin D1 overexpression. Cyclin D1 is associated with Akt1 and augments the rate of onset and maximal cellular Akt1 activity induced by mitogens. Cyclin D1 is identified in a cytoplasmic-membrane-associated pool, and cytoplasmic-membrane-localized cyclin D1-but not nuclear-localized cyclin D1-recapitulates Akt1 …
Structure-Based Screen Identifies A Potent Small Molecule Inhibitor Of Stat5a/B With Therapeutic Potential For Prostate Cancer And Chronic Myeloid Leukemia., Zhiyong Liao, Lei Gu, Jenny Vergalli, Samanta A. Mariani, Marco De Dominici, Ravi K. Lokareddy, Ayush Dagvadorj, Puranik Purushottamachar, Peter A. Mccue, Edouard J. Trabulsi, Costas D. Lallas, Shilpa Gupta, Elyse Ellsworth, Shauna Blackmon, Adam Ertel, Paolo Fortina, Benjamin E. Leiby, Guanjun Xia, Hallgeir Rui, David T. Hoang, Leonard G Gomella, Gino Cingolani, Vincent Njar, Nagarajan Pattabiraman, Bruno Calabretta, Marja T. Nevalainen
Structure-Based Screen Identifies A Potent Small Molecule Inhibitor Of Stat5a/B With Therapeutic Potential For Prostate Cancer And Chronic Myeloid Leukemia., Zhiyong Liao, Lei Gu, Jenny Vergalli, Samanta A. Mariani, Marco De Dominici, Ravi K. Lokareddy, Ayush Dagvadorj, Puranik Purushottamachar, Peter A. Mccue, Edouard J. Trabulsi, Costas D. Lallas, Shilpa Gupta, Elyse Ellsworth, Shauna Blackmon, Adam Ertel, Paolo Fortina, Benjamin E. Leiby, Guanjun Xia, Hallgeir Rui, David T. Hoang, Leonard G Gomella, Gino Cingolani, Vincent Njar, Nagarajan Pattabiraman, Bruno Calabretta, Marja T. Nevalainen
Department of Cancer Biology Faculty Papers
Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic …
Gsk3Β Inhibition Blocks Melanoma Cell/Host Interactions By Downregulating N-Cadherin Expression And Decreasing Fak Phosphorylation., Jobin K John, Kim H T Paraiso, Vito W Rebecca, Liliana P Cantini, Ethan V Abel, Nicholas Pagano, Eric Meggers, Rahel Mathew, Clemens Krepler, Victoria Izumi, Bin Fang, John M Koomen, Jane L Messina, Meenhard Herlyn, Keiran S M Smalley
Gsk3Β Inhibition Blocks Melanoma Cell/Host Interactions By Downregulating N-Cadherin Expression And Decreasing Fak Phosphorylation., Jobin K John, Kim H T Paraiso, Vito W Rebecca, Liliana P Cantini, Ethan V Abel, Nicholas Pagano, Eric Meggers, Rahel Mathew, Clemens Krepler, Victoria Izumi, Bin Fang, John M Koomen, Jane L Messina, Meenhard Herlyn, Keiran S M Smalley
Department of Cancer Biology Faculty Papers
This study addresses the role of glycogen synthase kinase (GSK)-3β signaling in the tumorigenic behavior of melanoma. Immunohistochemical staining revealed GSK3β to be focally expressed in the invasive portions of 12 and 33% of primary and metastatic melanomas, respectively. GSK3 inhibitors and small interfering RNA (siRNA) knockdown of GSK3β were found to inhibit the motile behavior of melanoma cells in scratch wound, three-dimensional collagen-implanted spheroid, and modified Boyden chamber assays. Functionally, inhibition of GSK3β signaling was found to suppress N-cadherin expression at the messenger RNA and protein levels, and was associated with decreased expression of the transcription factor Slug. Pharmacological …
Signal Transducer And Activator Of Transcription-5 Mediates Neuronal Apoptosis Induced By Inhibition Of Rac Gtpase Activity., Trisha R Stankiewicz, F Alexandra Loucks, Emily K Schroeder, Marja T Nevalainen, Kenneth L Tyler, Klaus Aktories, Ron J Bouchard, Daniel A Linseman
Signal Transducer And Activator Of Transcription-5 Mediates Neuronal Apoptosis Induced By Inhibition Of Rac Gtpase Activity., Trisha R Stankiewicz, F Alexandra Loucks, Emily K Schroeder, Marja T Nevalainen, Kenneth L Tyler, Klaus Aktories, Ron J Bouchard, Daniel A Linseman
Department of Cancer Biology Faculty Papers
In several neuronal cell types, the small GTPase Rac is essential for survival. We have shown previously that the Rho family GTPase inhibitor Clostridium difficile toxin B (ToxB) induces apoptosis in primary rat cerebellar granule neurons (CGNs) principally via inhibition of Rac GTPase function. In the present study, incubation with ToxB activated a proapoptotic Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and a pan-JAK inhibitor protected CGNs from Rac inhibition. STAT1 expression was induced by ToxB; however, CGNs from STAT1 knock-out mice succumbed to ToxB-induced apoptosis as readily as wild-type CGNs. STAT3 displayed enhanced tyrosine phosphorylation following …
Erk2 Phosphorylation Of Serine 77 Regulates Bmf Pro-Apoptotic Activity., Y Shao, A E Aplin
Erk2 Phosphorylation Of Serine 77 Regulates Bmf Pro-Apoptotic Activity., Y Shao, A E Aplin
Department of Cancer Biology Faculty Papers
B-cell lymphoma 2 (Bcl-2) homology 3 (BH3)-only proteins represent a class of pro-apoptotic factors that neutralize pro-survival Bcl-2 proteins, and, in some cases, directly activate Bax. The mechanisms of control and the role of BH3-only proteins, such as Bcl-2 like protein 11 extra large and Bad are well studied. By contrast, relatively little is known about the regulation and role of Bcl-2 modifying factor (Bmf). The B-RAF oncogene is mutated in ∼8% of human tumors. We have previously shown that Bmf is upregulated at the transcript level and is required for apoptosis induced by targeting B-RAF signaling in tumor cells …
Stat5 Regulation Of Bcl10 Parallels Constitutive Nfkappab Activation In Lymphoid Tumor Cells., Zsuzsanna S Nagy, Matthew J Lebaron, Jeremy A Ross, Abhisek Mitra, Hallgeir Rui, Robert A Kirken
Stat5 Regulation Of Bcl10 Parallels Constitutive Nfkappab Activation In Lymphoid Tumor Cells., Zsuzsanna S Nagy, Matthew J Lebaron, Jeremy A Ross, Abhisek Mitra, Hallgeir Rui, Robert A Kirken
Department of Cancer Biology Faculty Papers
BACKGROUND: Signal Transducer and Activator of Transcription 5 A and B (STAT5) are key survival factors in cells of the lymphoid lineage. Identification of novel, tissue-specific STAT5 regulated genes would advance the ability to combat diseases due to aberrant STAT5 signaling. In the present work a library of human STAT5 bound genomic elements was created and validated. RESULTS: Of several STAT5 responsive genomic regulatory elements identified, one was located within the first intron of the human BCL10 gene. Chromatin immuno-precipitation reactions confirmed constitutive in vivo STAT5 binding to this intronic fragment in various human lymphoid tumor cell lines. Interestingly, non-phosphorylated …
Cyclin D1 Repression Of Nuclear Respiratory Factor 1 Integrates Nuclear Dna Synthesis And Mitochondrial Function., Chenguang Wang, Zhiping Li, Yinan Lu, Runlei Du, Sanjay Katiyar, Jianguo Yang, Maofu Fu, Jennifer E Leader, Andrew Quong, Phyllis M Novikoff, Richard Pestell
Cyclin D1 Repression Of Nuclear Respiratory Factor 1 Integrates Nuclear Dna Synthesis And Mitochondrial Function., Chenguang Wang, Zhiping Li, Yinan Lu, Runlei Du, Sanjay Katiyar, Jianguo Yang, Maofu Fu, Jennifer E Leader, Andrew Quong, Phyllis M Novikoff, Richard Pestell
Department of Cancer Biology Faculty Papers
Cyclin D1 promotes nuclear DNA synthesis through phosphorylation and inactivation of the pRb tumor suppressor. Herein, cyclin D1 deficiency increased mitochondrial size and activity that was rescued by cyclin D1 in a Cdk-dependent manner. Nuclear respiratory factor 1 (NRF-1), which induces nuclear-encoded mitochondrial genes, was repressed in expression and activity by cyclin D1. Cyclin D1-dependent kinase phosphorylates NRF-1 at S47. Cyclin D1 abundance thus coordinates nuclear DNA synthesis and mitochondrial function.