المؤلفون: Li, Da-Qiang, Nair, Sujit S., Ohshiro, Kazufumi, Kumar, Anupam, Nair, Vasudha S., Pakala, Suresh B., Reddy, Sirigiri Divijendra Natha, Gajula, Rajendra P., Eswaran, Jeyanthy, Aravind, L., Kumar, Rakesh

المصدر: Cell Reports; Dec2012, Vol. 2 Issue 6, p1657-1669, 13p

مصطلحات موضوعية: ZINC-finger proteins, CELLULAR signal transduction, PHOSPHORYLATION, ADENOSINE triphosphatase, CHROMATIN, DNA damage

مستخلص: Summary: Chromatin dynamics play a central role in maintaining genome integrity, but how this is achieved remains largely unknown. Here, we report that microrchidia CW-type zinc finger 2 (MORC2), an uncharacterized protein with a derived PHD finger domain and a conserved GHKL-type ATPase module, is a physiological substrate of p21-activated kinase 1 (PAK1), an important integrator of extracellular signals and nuclear processes. Following DNA damage, MORC2 is phosphorylated on serine 739 in a PAK1-dependent manner, and phosphorylated MORC2 regulates its DNA-dependent ATPase activity to facilitate chromatin remodeling. Moreover, MORC2 associates with chromatin and promotes gamma-H2AX induction in a PAK1 phosphorylation-dependent manner. Consequently, cells expressing MORC2-S739A mutation displayed a reduction in DNA repair efficiency and were hypersensitive to DNA-damaging agent. These findings suggest that the PAK1-MORC2 axis is critical for orchestrating the interplay between chromatin dynamics and the maintenance of genomic integrity through sequentially integrating multiple essential enzymatic processes. [Copyright &y& Elsevier]

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المؤلفون: Pakala, Suresh B.¹, Nair, Vasudha S.¹, DivijendraNatha Reddy, Sirigiri¹, Kumar, Rakesh¹ bcmrxk@gwu.edu

المصدر: Journal of Biological Chemistry. 11/23/2012, Vol. 287 Issue 48, p40560-40569. 10p.

مصطلحات موضوعية: *PHOSPHORYLATION, *CELL cycle, *CENTROMERE, *KINESIN, *MICROTUBULES, *POLYMERIZATION, *P21 gene, *KINASES

مستخلص: Although p21-activated kinase 1 (PAK1) and microtubule (MT) dynamics regulate numerous fundamental processes including cytoskeleton remodeling, directional motility, and mitotic functions, the significance of PAK1 signaling in regulating the functions of MT-destabilizing protein mitotic centromere- associated kinesin (MCAK) remains unknown. Here we found thatMCAKis a cognate substrate of PAK1 wherein PAK1 phosphorylates MCAK on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that PAK1 phosphorylation of MCAKon serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes, respectively, in the mammalian cells. [ABSTRACT FROM AUTHOR]

المؤلفون: Reddy, Sirigiri Divijendra Natha¹, Pakala, Suresh B.¹, Molli, Poonam R.¹, Sahni, Neil¹, Karanam, Narasimha Kumar¹, Mudvari, Prakriti¹, Kumar, Rakesh¹ bcmrxk@gwu.edu

المصدر: Journal of Biological Chemistry. 8/10/2012, Vol. 287 Issue 33, p27843-27850. 8p.

مصطلحات موضوعية: *METASTASIS, *CANCER invasiveness, *BREAST cancer, *GENE expression, *TUMOR suppressor genes

مستخلص: Metastasis-associated protein 1 (MTA1) is widely overexpressed in human cancers and is associated with malignant phenotypic changes contributing to morbidity in the associated diseases. Here we discovered for the first time that MTA1, a master chromatin modifier, transcriptionally represses the expression of phosphatase and tensin homolog (PTEN), a tumor suppressor gene, by recruiting class II histone deacetylase 4 (HDAC4) along with the transcription factor Yin-Yang 1 (YY1) onto the PTEN promoter. We also found evidence of an inverse correlation between the expression levels of MTA1 and PTEN in physiologically relevant breast cancer microarray datasets.Wefound that MTA1 up-regulation leads to a decreased expression of PTEN protein and stimulation of PI3K as well as phosphorylation of its signaling targets. Accordingly, selective down-regulation of MTA1 in breast cancer cells increases PTEN expression and inhibits stimulation of the PI3K/AKT signaling. Collectively, these findings provide a mechanistic role for MTA1 in transcriptional repression of PTEN, leading to modulation of the resulting signaling pathways. [ABSTRACT FROM AUTHOR]

المؤلفون: Sankaran, Deivendran¹, Pakala, Suresh B.², Nair, Vasudha S.², Sirigiri, Divijendra Natha Reddy², Cyanam, Dinesh², Ngoc-Han Ha², Da-Qiang Li², Santhoshkumar, T. R.¹, Pillai, M. Radhakrishna¹ mrpillai@rgcb.res.in, Kumar, Rakesh^1,2 bcmrxk@gwumc.edu

المصدر: Journal of Biological Chemistry. 2/17/2012, Vol. 287 Issue 8, p5483-5491. 10p.

مصطلحات موضوعية: *BREAST cancer treatment, *SMALL interfering RNA, *CELL migration, *METASTASIS, *TUMOR antigens, *HYALURONIC acid

مستخلص: Even though the hyaluronan-mediated motility receptor (HMMR), a cell surface oncogenic protein, is widely up-regulated in human cancers and correlates well with cell motility and invasion, the underlying molecular and nature of its putative upstream regulation remain unknown. Here, we found for the first time that MTA1 (metastatic tumor antigen 1), a master chromatin modifier, regulates the expression of HMMR and, consequently, its function in breast cancer cell motility and invasiveness. We recognized a positive correlation between the levels of MTA1 and HMMR in human cancer. Furthermore, MTA1is required for optimal expression ofHMMR.The underlying mechanism includes interaction of the MTA1.RNA polymerase II.c-Jun coactivator complex with the HMMR promoter to stimulates its transcription. Accordingly, selective siRNA-mediated knockdown of HMMR in breast cancer cells substantially reduces the invasion and migration of cells. These findings reveal a regulatory role for MTA1 as an upstream coactivator of HMMR expression and resulting biological phenotypes. [ABSTRACT FROM AUTHOR]

المؤلفون: Lin Cong¹, Pakala, Suresh B.¹, Ohshiro, Kazufumi¹, Li, Da-Qiang¹, Kumar, Rakesh^1,2 bcmrxk@gwumc.edu

المصدر: Journal of Biological Chemistry. 12/23/2011, Vol. 286 Issue 51, p43793-43808. 16p.

مصطلحات موضوعية: *TUMOR antigens, *GENETIC transcription, *SMALL ubiquitin-related modifier proteins, *PROTEINS, *PROTEOLYTIC enzymes

مستخلص: Metastasis tumor antigen 1 (MTA1), a component of the Mi-2nucleosome remodeling and deacetylase complex, plays a crucial role in gene transcription, but the mechanism involved remains largely unknown. Here, we report that MTA1 is a substrate for small ubiquitin-related modifier 2/3 (SUMO2I3) in vivo. Protein inhibitor of activated STAT (PIAS) proteins enhance SUMOylation of MTA1 and may participate in paralog-selective SUMOylation, whereas sentrin/SUMO-specific protease 1 (SENP1) and 2 may act as deSUMOylation enzymes for MTA1. Moreover, MTA1 contains a functional SUMO-interacting motif (SIM) at its C terminus, and SIM is required for the efficient SUMOylation of MTA1, SUMO conjugation on Lys-509, which is located within the SUMO consensus site, together with SIM synergistically regulates the co-repressor activity of MTA1 on PS2 transcription, probably by recruiting HDAC2 onto the PS2 promoter. Interestingly, MTA1 may upregulate the expression of SUMO2 via interaction with RNA polymerase II and SP1 at the SUMO2 promoter. These findings not only provide novel mechanistic insights into the regulation of the transcriptional repressor function of MTA1 by SUMOylation and SIM but also uncover a potential function of MTA1 in modulating the SUMOylation pathway. [ABSTRACT FROM AUTHOR]

المؤلفون: Ghanta, Krishna Sumanth¹, Pakala, Suresh B.¹, Reddy, Sirigiri Divijendra Natha¹, Da-Qiang Li¹, Nair, Sujit S.¹, Kumar, Rakesh¹ bcmrxk@gwumc.edu

المصدر: Journal of Biological Chemistry. 3/4/2011, Vol. 286 Issue 9, p7132-7138. 7p.

مصطلحات موضوعية: *TUMOR antigens, *CHROMATIN, *TRANSGLUTAMINASES, *ENZYMES, *CELLS, *MACROPHAGES

مستخلص: Although both metastatic tumor antigen 1 (MTA1), a master chromatin modifier, and transglutaminase 2 (TG2), a multifunctional enzyme, are known to be activated during inflammation, it remains unknown whether these molecules regulate inflammatory response in a coordinated manner. Here we investigated the role of MTA1 in the regulation of TG2 expression in bacterial lipopolysaccharide (LPS)-stimulated mammalian cells. While studying the impact of MTA1 status on global gene expression, we unexpectedly discovered that MTA1 depletion impairs the basal as well as the LPS-induced expression of TG2 in multiple experimental systems. We found that TG2 is a chromatin target of MTA1 and of NF-κB signaling in LPS-stimulated cells. In addition, LPS-mediated stimulation of TG2 expression is accompanied by the enhanced recruitment of MTA1, p65RelA, and RNA polymerase II to the NF-κB consensus sites in the TG2 promoter. Interestingly, both the recruitment of p65 and TG2 expression are effectively blocked by a pharmacological inhibitor of the NF-κB pathway. These findings reveal an obligatory coregulatory role of MTA1 in the regulation of TG2 expression and of the MTA1-TG2 pathway, at least in part, in LPS modulation of the NF-κB signaling in stimulated macrophages. [ABSTRACT FROM AUTHOR]

المؤلفون: Pakala, Suresh B.¹, Bui-Nguyen, Tri M., Reddy, Sirigiri Divijendra Natha, Li, Da-Qiang², Peng, Shaohua³, Rayala, Suresh K.³, Behringer, Richard R.⁴, Kumar, Rakesh^2,3 bcmrxk@gwumc.edu

المصدر: Journal of Biological Chemistry. 7/30/2010, Vol. 285 Issue 31, p23590-23597. 8p. 7 Diagrams.

مصطلحات موضوعية: *TUMOR antigens, *CANCER, *ESCHERICHIA coli, *ENDOTOXINS, *MACROPHAGES, *CYTOKINES

مستخلص: The MTA1 coregulator (metastatic tumor antigen 1), a component of the nucleosome remodeling and deacetylase (NuRD) complex, has been intimately linked with human cancer, but its role in inflammatory responses remains unknown. Here, we discovered that MTAI is a target of inflammation, and stimulation of macrophages with Escherichia coli lipopolysaccharide (LPS) stimulates MTA1 transcription via the NF-ΚB pathway. Unexpectedly, we found that MTA1 depletion in LPS-stimulated macrophages impairs NF-ΚB signaling and expression of inflammatory molecules. MTA1 itself acts as a transcriptional coactivator of inflammatory cytokines in LPS-stimulated macrophages, and in contrast, it acts as a corepressor in resting primary macrophages as its depletion induced cytokine expression. LPS stimulates S-nitrosylation of histone deacetylase 2 (HDAC2) and interferes with its binding to MTA1, which, in turn, resulted in the loss of corepressor behavior of MTA1 x HDAC complex in activated macrophages. Consequently, the net levels of inflammatory cytokines in LPSstimulated macrophages from MTA1-/- mice were high compared with wild-type mice. Accordingly, MTA1-/- mice were much more susceptible than control mice to septic shock induced by LPS, revealing that MTA1 protects mice from deregulated host inflammatory response. These findings reveal a previously unrecognized, critical homeostatic role of MTA1, both as a target and as a component of the NF-ΚB circuitry, in the regulation of inflammatory responses. [ABSTRACT FROM AUTHOR]

المؤلفون: Da-Qiang Li¹, Pakala, Suresh B.¹, Reddy, Sirigiri Divijendra Natha¹, Ohshiro, Kazufumi¹, Shao-Hua Peng¹, Lian, Vi¹, Fu, Sidney W.¹, Kumar, Rakesh¹ bcmrxk@gwumc.edu

المصدر: Journal of Biological Chemistry. 3/26/2010, Vol. 285 Issue 13, p10044-10052. 9p.

مصطلحات موضوعية: *P53 antioncogene, *P53 protein, *TUMOR suppressor proteins, *CELL proliferation, *DNA damage, *CARCINOGENESIS, *LIGASES

مستخلص: Although metastasis-associated protein 1 (MTA1), a component of the nucleosome remodeling and deacetylase (NuRD) complex, is a DNA-damage response protein and regulates p53dependent DNA repair, it remains unknown whether MTA1 also participates in p53-independent DNA damage response. Here, we provide evidence that MTA1 is a p53-independent transcriptional corepressor of p21 WAF1, and the underlying mechanism involves recruitment of MTA1-histone deacetylase 2 (HDAC2) complexes onto two selective regions of the p21 WAF1 promoter. Accordingly, MTA1 depletion, despite its effect on p53 down-regulation, superinduces p21 WAF1, increases p21 WAF1 binding to proliferating cell nuclear antigen (PCNA), and decreases the nuclear accumulation of PCNA in response to ionizing radiation. In support of a p53-independent role of MTA1 in DNA damage response, we further demonstrate that induced expression of MTA1 in p53-null cells inhibits p21W promoter activity and p21WAF1 binding to PCNA. Consequently, MTA1 expression in p53-null cells results in increased induction of γH2AX foci and DNA double strand break repair, and decreased DNA damage sensitivity following ionizing radiation treatment. These findings uncover a new target of MTA1 and the existence of an additional p53-independent role of MTA1 in DNA damage response, at least in part, by modulating the p2WAF1-PCNA pathway, and thus, linking two previously unconnected NuRD complex and DNA-damage response pathways. [ABSTRACT FROM AUTHOR]

المؤلفون: Bui-Nguyen, Tri M.¹, Pakala, Suresh B.¹, Sirigiri, Divijendranatha Reddy¹, Martins, Emil², Murad, Ferid², Kumar, Rakesh¹ bcmrxk@gwumc.edu

المصدر: Journal of Biological Chemistry. 3/5/2010, Vol. 285 Issue 10, p6980-6986. 7p.

مصطلحات موضوعية: *NITRIC oxide, *HEPATITIS B virus, *LIVER cancer, *LIVER cells, *NON-coding RNA, *NITRIC-oxide synthases, *CANCER cells, *NF-kappa B

مستخلص: Nitric oxide has been implicated in the pathogenesis of inflammatory disorders, including hepatitis B virus-associated hepatocellular carcinoma. Transactivator protein HBx, a major regulator of cellular responses of hepatitis B virus, is known to induce the expression of MTA1 (metastasis-associated protein 1) coregulator via NF-κB signaling in hepatic cells. However, the underlying mechanism of HBx regulation of the inducible nitric-oxide synthase (iNOS) pathway remains unknown. Here we provide evidence that MTA1 is a positive regulator of iNOS transcription and plays a mechanistic role in HBx stimulation of iNOS expression and activity. We found that the HBx-MTA1 complexisrecruitedontothe human iNOS promoterinan NF-κB-dependent manner. Pharmacological inhibition of the NF-κB signaling prevented the ability of HBx to stimulate the transcription, the expression, and the activity of iNOS; nevertheless, these effects could be substantially rescued by MTA1 dysregulation. We further discovered that HBx-mediated stimulation of MTA1 is paralleled by the suppression of miR-661, a member of the small noncoding RNAs, recently shown to target MTA1. We observed that miR-661 controls of MTA1 expression contributed to the expression and activity of iNOS in HBx-expressing HepG2 cells. Accordingly, depletion of MTA1 by either miR-661 or siRNA in HBx-expressing cells severely impaired the ability of HBx to modulate the endogenous levels of iNOS and nitrite production. Together, these findings reveal an inherent role of MTA1 in HBx regulation of iNOS expression and consequently its function in the liver cancer cells. [ABSTRACT FROM AUTHOR]

المؤلفون: Da-Qiang Li¹, Reddy, Sirigiri Divijendra Natha¹, Pakala, Suresh B.¹, Xifeng Wu², Yanping Zhang³, Rayala, Suresh K.¹, Kumar, Rakesh¹ bcmrxk@gwumc.edu

المصدر: Journal of Biological Chemistry. 12/11/2009, Vol. 284 Issue 50, p34545-34552. 8p.

مصطلحات موضوعية: *P53 protein, *DNA damage, *DOUBLE-stranded RNA, *NUCLEOTIDES, *DNA repair, *CANCER cells

مستخلص: Although metastasis-associated protein 1 (MTA1) has recently been shown as a DNA damage responsive protein, the underlying mechanism for its role in DNA double-strand break (DSB) repair remains unknown. Here, we show that MTA1 controls p53 stability through inhibiting its ubiquitination by E3 ubiquitin ligases mouse double minute 2 (Mdm2) and constitutive photomorphogenic protein 1 (COP1). The underlying mechanisms involve the ability ofMTA1 to compete with COP! to bind to p53 and/or to destabilize COP1 and Mdm2. Consequently, MTA1 regulates the p53-dependent transcription of p53R2, a direct p53 target gene for supplying nucleotides to repair damaged DNA. Depletion of MTA1 impairs p53-dependent p53R2 transcription and compromises DNA repair. Interestingly, these events could be reversed by MTA1 reintroduction, indicating that MTA1 interjects into the p53-dependent DNA repair. Given the fact that MTA1 is widely up-regulated in human cancers, these findings in conjunction with our earlier finding of a crucial role ofMTA1 in DSB repair suggest an inherent role of the MTA1-p53-p53R2 pathway in DNA damage response in cancer cells. [ABSTRACT FROM AUTHOR]