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Rajini Rao - One of the best experts on this subject based on the ideXlab platform.
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abstract 5276 secretory pathway Calcium ATPase 2 spca2 promotes cell survival and chemoresistance in receptor positive breast cancer cells
Cancer Research, 2020Co-Authors: Monish Ram Makena, Donna K Dang, Allatah Mekile, Phillip Buckhaults, Rajini RaoAbstract:Introduction: Dysregulation of the Ca2+ toolkit has profound consequences for tumor growth and metastasis, raising hopes for novel avenues of therapeutic intervention. The Secretory Pathway Ca2+-ATPase Isoform 2 (SPCA2) has a dual function in sequestering Ca2+ and Mn2+ into secretory stores as well as eliciting their entry into cells by activating plasma membrane ion channels. We have previously showed that SPCA2 is implicated in breast cancer progression, microcalcifications, epithelial-mesenchymal transition, and metastasis. Methods and Results: High SPCA2 expression was associated with poor overall survival in receptor positive breast cancer patients (n=548, P =8.7e-0.6; KM Plotter). Depletion of SPCA2 (SPCA2 KD) in MCF-7 cells significantly reduced cell proliferation (P Conclusion: These novel findings point to a causal link between SPCA2, breast cancer progression, and chemoresistance to DNA damaging agents. Decrease of SPCA2 expression by curcumin may have therapeutic potential in treating receptor positive breast cancer. Citation Format: Monish Ram Makena, Donna Dang, Allatah Mekile, Phillip Buckhaults, Rajini Rao. Secretory pathway Calcium ATPase 2 (SPCA2) promotes cell survival and chemoresistance in receptor positive breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5276.
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abstract 1125 secretory pathway Calcium ATPase 2 spca2 regulates metastasis by suppressing mesenchymal markers in triple negative breast cancer cell lines
Cancer Research, 2019Co-Authors: Monish Ram Makena, Donna K Dang, Manuj Bandral, Rajini RaoAbstract:Introduction: Over 90% of cancer deaths in breast cancer are associated with metastasis. Epithelial-mesenchymal transition (EMT) is the hallmark of metastasis. Dysregulation of the Ca2+ toolkit has profound consequences for tumor growth and metastasis, raising hopes for novel avenues of therapeutic intervention. The Secretory Pathway Ca2+-ATPase Isoform 2 (SPCA2) transports Ca2+ from cytoplasm to the Golgi, and elicits Ca2+ influx by interacting with plasma membrane Ca2+ channels. Previously, we showed that SPCA2 is implicated in breast cancer progression (Feng et al., Cell 2010). Furthermore, low SPCA2 expression is associated with triple negative breast cancers (TNBC), which are highly metastatic. Therefore, we investigated if ectopic expression of SPCA2 modulates EMT in TNBC cell lines. Methods: TCGA invasive breast carcinoma project datasets were accessed through cBioPortal. Gene expression was determined by qPCR and protein expression by Immunoblotting and confocal microscopy. Live cell Calcium imaging was performed using Fura-2 AM dye. NSG mice were used for in vivo studies. Results: Low SPCA2 expression was associated with poor survival in TNBC patients (n=255, P Conclusion: These novel findings point to a causal link between low SPCA2 levels, poor prognosis, and the epithelial-mesenchymal transition required for breast cancer metastasis. Restoration of SPCA2 expression in TNBC by HDAC inhibitors may have therapeutic potential. Citation Format: Monish Ram Makena, Donna K. Dang, Myungjun Ko, Manuj Bandral, Rajini Rao. Secretory pathway Calcium ATPase-2 (SPCA2) regulates metastasis by suppressing mesenchymal markers in triple negative breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1125.
Monish Ram Makena - One of the best experts on this subject based on the ideXlab platform.
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abstract 5276 secretory pathway Calcium ATPase 2 spca2 promotes cell survival and chemoresistance in receptor positive breast cancer cells
Cancer Research, 2020Co-Authors: Monish Ram Makena, Donna K Dang, Allatah Mekile, Phillip Buckhaults, Rajini RaoAbstract:Introduction: Dysregulation of the Ca2+ toolkit has profound consequences for tumor growth and metastasis, raising hopes for novel avenues of therapeutic intervention. The Secretory Pathway Ca2+-ATPase Isoform 2 (SPCA2) has a dual function in sequestering Ca2+ and Mn2+ into secretory stores as well as eliciting their entry into cells by activating plasma membrane ion channels. We have previously showed that SPCA2 is implicated in breast cancer progression, microcalcifications, epithelial-mesenchymal transition, and metastasis. Methods and Results: High SPCA2 expression was associated with poor overall survival in receptor positive breast cancer patients (n=548, P =8.7e-0.6; KM Plotter). Depletion of SPCA2 (SPCA2 KD) in MCF-7 cells significantly reduced cell proliferation (P Conclusion: These novel findings point to a causal link between SPCA2, breast cancer progression, and chemoresistance to DNA damaging agents. Decrease of SPCA2 expression by curcumin may have therapeutic potential in treating receptor positive breast cancer. Citation Format: Monish Ram Makena, Donna Dang, Allatah Mekile, Phillip Buckhaults, Rajini Rao. Secretory pathway Calcium ATPase 2 (SPCA2) promotes cell survival and chemoresistance in receptor positive breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5276.
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abstract 1125 secretory pathway Calcium ATPase 2 spca2 regulates metastasis by suppressing mesenchymal markers in triple negative breast cancer cell lines
Cancer Research, 2019Co-Authors: Monish Ram Makena, Donna K Dang, Manuj Bandral, Rajini RaoAbstract:Introduction: Over 90% of cancer deaths in breast cancer are associated with metastasis. Epithelial-mesenchymal transition (EMT) is the hallmark of metastasis. Dysregulation of the Ca2+ toolkit has profound consequences for tumor growth and metastasis, raising hopes for novel avenues of therapeutic intervention. The Secretory Pathway Ca2+-ATPase Isoform 2 (SPCA2) transports Ca2+ from cytoplasm to the Golgi, and elicits Ca2+ influx by interacting with plasma membrane Ca2+ channels. Previously, we showed that SPCA2 is implicated in breast cancer progression (Feng et al., Cell 2010). Furthermore, low SPCA2 expression is associated with triple negative breast cancers (TNBC), which are highly metastatic. Therefore, we investigated if ectopic expression of SPCA2 modulates EMT in TNBC cell lines. Methods: TCGA invasive breast carcinoma project datasets were accessed through cBioPortal. Gene expression was determined by qPCR and protein expression by Immunoblotting and confocal microscopy. Live cell Calcium imaging was performed using Fura-2 AM dye. NSG mice were used for in vivo studies. Results: Low SPCA2 expression was associated with poor survival in TNBC patients (n=255, P Conclusion: These novel findings point to a causal link between low SPCA2 levels, poor prognosis, and the epithelial-mesenchymal transition required for breast cancer metastasis. Restoration of SPCA2 expression in TNBC by HDAC inhibitors may have therapeutic potential. Citation Format: Monish Ram Makena, Donna K. Dang, Myungjun Ko, Manuj Bandral, Rajini Rao. Secretory pathway Calcium ATPase-2 (SPCA2) regulates metastasis by suppressing mesenchymal markers in triple negative breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1125.
Howard S Young - One of the best experts on this subject based on the ideXlab platform.
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protein docking and steered molecular dynamics reveal alternative regulatory sites on the serca Calcium transporter
bioRxiv, 2019Co-Authors: Rebecca F Alford, Nikolai Smolin, Howard S Young, Jeffrey J Gray, Seth L. RobiaAbstract:The transport activity of the Calcium ATPase SERCA is modulated by an inhibitory interaction with a 52-residue transmembrane peptide, phospholamban (PLB). Biochemical and structural studies have revealed the primary inhibitory site on SERCA, but PLB has been hypothesized to interact with alternative sites on SERCA that are distinct from the inhibitory site. The present study was undertaken to test these hypotheses and explore structural determinants of SERCA regulation by PLB. Steered molecular dynamics (SMD) and membrane protein-protein docking experiments were performed to investigate the apparent affinity of PLB interactions with candidate sites on SERCA. We modeled the relative binding of PLB to several different conformations of SERCA, representing different enzymatic states sampled during the Calcium transport catalytic cycle. Overall, the SMD and docking experiments suggest that the canonical binding site is preferred, but also provide evidence for alternative sites that are favorable for certain conformational states of SERCA.
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phospholamban c terminal residues are critical determinants of the structure and function of the Calcium ATPase regulatory complex
Journal of Biological Chemistry, 2014Co-Authors: Neha Abrol, Howard S Young, Nikolai Smolin, Gareth P Armanious, Delaine K Ceholski, Catharine A Trieber, Seth L. RobiaAbstract:To determine the structural and regulatory role of the C-terminal residues of phospholamban (PLB) in the membranes of living cells, we fused fluorescent protein tags to PLB and sarco/endoplasmic reticulum Calcium ATPase (SERCA). Alanine substitution of PLB C-terminal residues significantly altered fluorescence resonance energy transfer (FRET) from PLB to PLB and SERCA to PLB, suggesting a change in quaternary conformation of PLB pentamer and SERCA-PLB regulatory complex. Val to Ala substitution at position 49 (V49A) had particularly large effects on PLB pentamer structure and PLB-SERCA regulatory complex conformation, increasing and decreasing probe separation distance, respectively. We also quantified a decrease in oligomerization affinity, an increase in binding affinity of V49A-PLB for SERCA, and a gain of inhibitory function as quantified by Calcium-dependent ATPase activity. Notably, deletion of only a few C-terminal residues resulted in significant loss of PLB membrane anchoring and mislocalization to the cytoplasm and nucleus. C-terminal truncations also resulted in progressive loss of PLB-PLB FRET due to a decrease in the apparent affinity of PLB oligomerization. We quantified a similar decrease in the binding affinity of truncated PLB for SERCA and loss of inhibitory potency. However, despite decreased SERCA-PLB binding, intermolecular FRET for Val49-stop (V49X) truncation mutant was paradoxically increased as a result of an 11.3-Å decrease in the distance between donor and acceptor fluorophores. We conclude that PLB C-terminal residues are critical for localization, oligomerization, and regulatory function. In particular, the PLB C terminus is an important determinant of the quaternary structure of the SERCA regulatory complex.
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sarco endo plasmic reticulum Calcium ATPase serca inhibition by sarcolipin is encoded in its luminal tail
Journal of Biological Chemistry, 2013Co-Authors: Przemek A Gorski, John Paul Glaves, Peter Vangheluwe, Howard S YoungAbstract:The sarco(endo)plasmic reticulum Calcium ATPase (SERCA) is regulated in a tissue-dependent manner via interaction with the short integral membrane proteins phospholamban (PLN) and sarcolipin (SLN). Although defects in SERCA activity are known to cause heart failure, the regulatory mechanisms imposed by PLN and SLN could have clinical implications for both heart and skeletal muscle diseases. PLN and SLN have significant sequence homology in their transmembrane regions, suggesting a similar mode of binding to SERCA. However, unlike PLN, SLN has a conserved C-terminal luminal tail composed of five amino acids (27RSYQY), which may contribute to a distinct SERCA regulatory mechanism. We have functionally characterized alanine mutants of the C-terminal tail of SLN using co-reconstituted proteoliposomes of SERCA and SLN. We found that Arg27 and Tyr31 are essential for SLN function. We also tested the effect of a truncated variant of SLN (Arg27stop) and extended chimeras of PLN with the five luminal residues of SLN added to its C terminus. The Arg27stop form of SLN resulted in loss of function, whereas the PLN chimeras resulted in superinhibition with characteristics of both PLN and SLN. Based on our results, we propose that the C-terminal tail of SLN is a distinct, essential domain in the regulation of SERCA and that the functional properties of the SLN tail can be transferred to PLN.
Stella Elkabes - One of the best experts on this subject based on the ideXlab platform.
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a link between plasma membrane Calcium ATPase 2 pmca2 estrogen and estrogen receptor α signaling in mechanical pain
Scientific Reports, 2018Co-Authors: Veronika Khariv, Cigdem Acioglu, Ayomi Ratnayake, Yuan Xiang Tao, Robert F Heary, Stella ElkabesAbstract:Earlier studies on genetically modified mice indicated that plasma membrane Calcium ATPase 2 (PMCA2), a Calcium extrusion pump, plays a novel and sex-dependent role in mechanical pain responses: female, but not male, PMCA2+/- mice manifest increased mechanical pain compared to female PMCA2+/+ mice. The goal of the present studies was to determine the contribution of ovarian steroids to the genotype- and sex-dependent manifestation of mechanical pain in PMCA2+/+ versus PMCA2+/- mice. Ovariectomy increased mechanical pain sensitivity and 17β-estradiol (E2) replacement restored it to basal levels in PMCA2+/+ mice, but not in PMCA2+/- littermates. Intrathecal administration of an estrogen receptor alpha (ERα) agonist induced ERα signaling in the dorsal horn (DH) of female PMCA2+/+ mice, but was ineffective in PMCA2+/- mice. In male PMCA2+/+ and PMCA2+/- mice, E2 treatment following orchidectomy did not recapitulate the genotype-dependent differential pain responses observed in females and the agonist did not elicit ERα signaling. These findings establish a novel, female-specific link between PMCA2, ERα and mechanical pain. It is postulated that PMCA2 is essential for adequate ERα signaling in the female DH and that impaired ERα signaling in the female PMCA2+/- mice hinders the analgesic effects of E2 leading to increased sensitivity to mechanical stimuli.
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plasma membrane Calcium ATPase deficiency causes neuronal pathology in the spinal cord a potential mechanism for neurodegeneration in multiple sclerosis and spinal cord injury
The FASEB Journal, 2005Co-Authors: Michael P Kurnellas, Stella Elkabes, Arnaud Nicot, Gary E ShullAbstract:Dysfunction and death of spinal cord neurons are critical determinants of neurological deficits in various pathological conditions, including multiple sclerosis (MS) and spinal cord injury. Yet, the molecular mechanisms underlying neuronal/axonal damage remain undefined. Our previous studies raised the possibility that a decrease in the levels of plasma membrane Calcium ATPase isoform 2 (PMCA2), a major pump extruding Calcium from neurons, promotes neuronal pathology in the spinal cord during experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and after spinal cord trauma. However, the causal relationship between alterations in PMCA2 levels and neuronal injury was not well established. We now report that inhibition of PMCA activity in purified spinal cord neuronal cultures delays Calcium clearance, increases the number of nonphosphorylated neurofilament H (SMI-32) immunoreactive cells, and induces swelling and beading of SMI-32-positive neurites. These changes are followed by activation of caspase-3 and neuronal loss. Importantly, the number of spinal cord motor neurons is significantly decreased in PMCA2-deficient mice and the deafwaddler(2J), a mouse with a functionally null mutation in the PMCA2 gene. Our findings suggest that a reduction in PMCA2 level or activity leading to delays in Calcium clearance may cause neuronal damage and loss in the spinal cord.
Donna K Dang - One of the best experts on this subject based on the ideXlab platform.
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abstract 5276 secretory pathway Calcium ATPase 2 spca2 promotes cell survival and chemoresistance in receptor positive breast cancer cells
Cancer Research, 2020Co-Authors: Monish Ram Makena, Donna K Dang, Allatah Mekile, Phillip Buckhaults, Rajini RaoAbstract:Introduction: Dysregulation of the Ca2+ toolkit has profound consequences for tumor growth and metastasis, raising hopes for novel avenues of therapeutic intervention. The Secretory Pathway Ca2+-ATPase Isoform 2 (SPCA2) has a dual function in sequestering Ca2+ and Mn2+ into secretory stores as well as eliciting their entry into cells by activating plasma membrane ion channels. We have previously showed that SPCA2 is implicated in breast cancer progression, microcalcifications, epithelial-mesenchymal transition, and metastasis. Methods and Results: High SPCA2 expression was associated with poor overall survival in receptor positive breast cancer patients (n=548, P =8.7e-0.6; KM Plotter). Depletion of SPCA2 (SPCA2 KD) in MCF-7 cells significantly reduced cell proliferation (P Conclusion: These novel findings point to a causal link between SPCA2, breast cancer progression, and chemoresistance to DNA damaging agents. Decrease of SPCA2 expression by curcumin may have therapeutic potential in treating receptor positive breast cancer. Citation Format: Monish Ram Makena, Donna Dang, Allatah Mekile, Phillip Buckhaults, Rajini Rao. Secretory pathway Calcium ATPase 2 (SPCA2) promotes cell survival and chemoresistance in receptor positive breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5276.
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abstract 1125 secretory pathway Calcium ATPase 2 spca2 regulates metastasis by suppressing mesenchymal markers in triple negative breast cancer cell lines
Cancer Research, 2019Co-Authors: Monish Ram Makena, Donna K Dang, Manuj Bandral, Rajini RaoAbstract:Introduction: Over 90% of cancer deaths in breast cancer are associated with metastasis. Epithelial-mesenchymal transition (EMT) is the hallmark of metastasis. Dysregulation of the Ca2+ toolkit has profound consequences for tumor growth and metastasis, raising hopes for novel avenues of therapeutic intervention. The Secretory Pathway Ca2+-ATPase Isoform 2 (SPCA2) transports Ca2+ from cytoplasm to the Golgi, and elicits Ca2+ influx by interacting with plasma membrane Ca2+ channels. Previously, we showed that SPCA2 is implicated in breast cancer progression (Feng et al., Cell 2010). Furthermore, low SPCA2 expression is associated with triple negative breast cancers (TNBC), which are highly metastatic. Therefore, we investigated if ectopic expression of SPCA2 modulates EMT in TNBC cell lines. Methods: TCGA invasive breast carcinoma project datasets were accessed through cBioPortal. Gene expression was determined by qPCR and protein expression by Immunoblotting and confocal microscopy. Live cell Calcium imaging was performed using Fura-2 AM dye. NSG mice were used for in vivo studies. Results: Low SPCA2 expression was associated with poor survival in TNBC patients (n=255, P Conclusion: These novel findings point to a causal link between low SPCA2 levels, poor prognosis, and the epithelial-mesenchymal transition required for breast cancer metastasis. Restoration of SPCA2 expression in TNBC by HDAC inhibitors may have therapeutic potential. Citation Format: Monish Ram Makena, Donna K. Dang, Myungjun Ko, Manuj Bandral, Rajini Rao. Secretory pathway Calcium ATPase-2 (SPCA2) regulates metastasis by suppressing mesenchymal markers in triple negative breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1125.