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  • 1
    Online Resource
    Online Resource
    In Vivo Deletion of β-Cell Drp1 Impairs Insulin Secretion Without Affecting Islet Oxygen Consumption
    The Endocrine Society ; 2018
    In:  Endocrinology Vol. 159, No. 9 ( 2018-09-01), p. 3245-3256
    Details
    In: Endocrinology, The Endocrine Society, Vol. 159, No. 9 ( 2018-09-01), p. 3245-3256
    Abstract: Mitochondria are dynamic organelles that undergo frequent fission and fusion events. Mitochondrial fission is required for ATP production, the tricarboxylic acid cycle, and processes beyond metabolism in a cell-type specific manner. Ex vivo and cell line studies have demonstrated that Drp1, a central regulator of mitochondrial fission, is required for glucose-stimulated insulin secretion (GSIS) in pancreatic β cells. Herein, we set out to interrogate the role of Drp1 in β-cell insulin secretion in vivo. We generated β-cell–specific Drp1 knockout (KO) mice (Drp1β-KO) by crossing a conditional allele of Drp1 to Ins1cre mice, in which Cre recombinase replaces the coding region of the Ins1 gene. Drp1β-KO mice were glucose intolerant due to impaired GSIS but did not progress to fasting hyperglycemia as adults. Despite markedly abnormal mitochondrial morphology, Drp1β-KO islets exhibited normal oxygen consumption rates and an unchanged glucose threshold for intracellular calcium mobilization. Instead, the most profound consequences of β-cell Drp1 deletion were impaired second-phase insulin secretion and impaired glucose-stimulated amplification of insulin secretion. Our data establish Drp1 as an important regulator of insulin secretion in vivo and demonstrate a role for Drp1 in metabolic amplification and calcium handling without affecting oxygen consumption.
    Type of Medium: Online Resource
    ISSN: 1945-7170
    URL: Article
    DOI: 10.1210/en.2018-00445
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2018
    detail.hit.zdb_id: 2011695-0
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  • 2
    Online Resource
    Online Resource
    Targeting RET Kinase in Neuroendocrine Prostate Cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Molecular Cancer Research Vol. 18, No. 8 ( 2020-08-01), p. 1176-1188
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 8 ( 2020-08-01), p. 1176-1188
    Abstract: The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR-independent tumors may also transdifferentiate to express neuroendocrine lineage markers and are termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing several AR-independent to AR-dependent prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-independent cell lines. Clinical NEPC patient samples and NEPC patient-derived xenografts displayed upregulated RET transcript and RET pathway activity. Genetic knockdown or pharmacologic inhibition of RET kinase in multiple mouse and human models of NEPC dramatically reduced tumor growth and decreased cell viability. Our results suggest that targeting RET in NEPC tumors with high RET expression could be an effective treatment option. Currently, there are limited treatment options for patients with aggressive neuroendocrine prostate cancer and none are curative. Implications: Identification of aberrantly expressed RET kinase as a driver of tumor growth in multiple models of NEPC provides a significant rationale for testing the clinical application of RET inhibitors in patients with AVPC.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-19-1245
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Human cytomegalovirus-encoded viral cyclin-dependent kinase (v-CDK) UL97 phosphorylates and inactivates the retinoblastoma protein-related p107 and p130 proteins
    Elsevier BV ; 2017
    In:  Journal of Biological Chemistry Vol. 292, No. 16 ( 2017-04), p. 6583-6599
    Details
    In: Journal of Biological Chemistry, Elsevier BV, Vol. 292, No. 16 ( 2017-04), p. 6583-6599
    Type of Medium: Online Resource
    ISSN: 0021-9258
    URL: Article
    DOI: 10.1074/jbc.M116.773150
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 2141744-1
    detail.hit.zdb_id: 1474604-9
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Radiomanganese PET Detects Changes in Functional β-Cell Mass in Mouse Models of Diabetes
    American Diabetes Association ; 2017
    In:  Diabetes Vol. 66, No. 8 ( 2017-08-01), p. 2163-2174
    Details
    In: Diabetes, American Diabetes Association, Vol. 66, No. 8 ( 2017-08-01), p. 2163-2174
    Abstract: The noninvasive measurement of functional β-cell mass would be clinically valuable for monitoring the progression of type 1 and type 2 diabetes as well as the viability of transplanted insulin-producing cells. Although previous work using MRI has shown promise for functional β-cell mass determination through voltage-dependent Ca2+ channel (VDCC)–mediated internalization of Mn2+, the clinical utility of this technique is limited by the cytotoxic levels of the Mn2+ contrast agent. Here, we show that positron emission tomography (PET) is advantageous for determining functional β-cell mass using 52Mn2+ (t1/2: 5.6 days). We investigated the whole-body distribution of 52Mn2+ in healthy adult mice by dynamic and static PET imaging. Pancreatic VDCC uptake of 52Mn2+ was successfully manipulated pharmacologically in vitro and in vivo using glucose, nifedipine (VDCC blocker), the sulfonylureas tolbutamide and glibenclamide (KATP channel blockers), and diazoxide (KATP channel opener). In a mouse model of streptozotocin-induced type 1 diabetes, 52Mn2+ uptake in the pancreas was distinguished from healthy controls in parallel with classic histological quantification of β-cell mass from pancreatic sections. 52Mn2+-PET also reported the expected increase in functional β-cell mass in the ob/ob model of pretype 2 diabetes, a result corroborated by histological β-cell mass measurements and live-cell imaging of β-cell Ca2+ oscillations. These results indicate that 52Mn2+-PET is a sensitive new tool for the noninvasive assessment of functional β-cell mass.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db16-1285
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2017
    detail.hit.zdb_id: 1501252-9
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  • 5
    Online Resource
    Online Resource
    Deficiencies in Cellular Processes Modulated by the Retinoblastoma Protein Do Not Account for Reduced Human Cytomegalovirus Replication in Its Absence
    American Society for Microbiology ; 2015
    In:  Journal of Virology Vol. 89, No. 23 ( 2015-12), p. 11965-11974
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 89, No. 23 ( 2015-12), p. 11965-11974
    Abstract: Despite encoding multiple viral proteins that modulate the retinoblastoma (Rb) protein in a manner classically defined as inactivation, human cytomegalovirus (HCMV) requires the presence of the Rb protein to replicate efficiently. In uninfected cells, Rb controls numerous pathways that the virus also commandeers during infection. These include cell cycle progression, senescence, mitochondrial biogenesis, apoptosis, and glutaminolysis. We investigated whether a potential inability of HCMV to regulate these Rb-controlled pathways in the absence of the Rb protein was the reason for reduced viral productive replication in Rb knockdown cells. We found that HCMV was equally able to modulate these pathways in the parental Rb-expressing and Rb-depleted cells. Our results suggest that Rb may be required to enhance a specific viral process during HCMV productive replication. IMPORTANCE The retinoblastoma (Rb) tumor suppressor is well established as a repressor of E2F-dependent transcription. Rb hyperphosphorylation, degradation, and binding by viral oncoproteins are also codified. Recent reports indicate Rb can be monophosphorylated, repress the transcription of antiviral genes in association with adenovirus E1A, modulate cellular responses to polycomb-mediated epigenetic methylations in human papillomavirus type 16 E7 expressing cells, and increase the efficiency of human cytomegalovirus (HCMV) productive replication. Since Rb function also now extends to regulation of mitochondrial function (apoptosis, metabolism), it is clear that our current understanding of this protein is insufficient to explain its roles in virus-infected cells and tumors. Work here reinforces this concept, showing the known roles of Rb are insufficient to explain its positive impact on HCMV replication. Therefore, HCMV, along with other viral systems, provide valuable tools to probe functions of Rb that might be modulated with therapeutics for cancers with viral or nonviral etiologies.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01718-15
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2015
    detail.hit.zdb_id: 1495529-5
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  • 6
    Online Resource
    Online Resource
    127-OR: In Vivo Genetic Evidence That the Pyruvate Kinase Isoforms PKM1 and PKM2 Differentially Control Beta-Cell Fuel Sensing
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. Supplement_1 ( 2021-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
    Abstract: Pancreatic β-cells couple nutrient metabolism with appropriate insulin secretion. Here, we examined the requirements of pyruvate kinase (PK) isoforms in fuel sensing through the β-cell specific deletion of consititutively active PKM1 and allosterically recruitable PKM2 (PKM1- βKO, PKM2-βKO). β-cell deletion of PEP carboxykinase (PCK2-βKO) was used to block mitochondrial PEP production, leaving glycolytic PEP production intact. In vivo, only the PKM1-βKO mice showed glucose intolerance, and ex vivo insulin secretion was correspondingly reduced. Glucose-dependent Ca2+ oscillations were comparable in PKM1 βKO and PKM2-βKO islets, while the oscillatory frequency and duty cycle in PCK2-βKO islets increased relative to controls, suggesting redundancy in the PK response to glycolytic but not mitochondrial PEP. Using direct single-channel measurements of KATP in intact β-cells, amino acids were sufficient to stimulate KATP closure in control and PKM2-βKO cells, but failed to do so in the PCK2-βKO and PKM1-βKO models. PK activators (PKa) rescued KATP closure in PKM1- but not PCK2-deficient β-cells, arguing that PKM1 and PCK2 mediate membrane depolarization in response to mitochondrial fuels. The dependence of PKM2 on glucose was confirmed by the ability of PKa to rescue KATP closure in excised membrane patches from PKM1-βKO mice. Consistently, calcium influx stimulated by amino acids at low glucose was deficient in islets from PKM1-βKO and PCK2-βKO mice. PKa was sufficient to rescue the calcium defect in the PKM1-βKO islets but did not fully rescue the PCK2-βKO. Our findings provide strong genetic and electrophysiological evidence that the PCK2-PKM1 pathway is uniquely suited to direct the active (secretory) phase of calcium oscillations through direct effects on KATP, when FBP is low and PKM2 is inactive. While more limited in function, PKM2 can be therapeutically targeted, endowing it with the ability to respond to mitochondrial PEP and boost insulin secretion. Disclosure H. R. Foster: None. T. Ho: None. E. Potapenko: None. S. L. Lewandowski: None. S. Sdao: None. H. R. Vandeusen: None. R. L. Cardone: None. R. Kibbey: Research Support; Self; Agios, Inc. M. J. Merrins: None. Funding Health Resources and Services Administration (T32HP10010); National Institute on Aging (T32AG000213); National Institutes of Health (R01DK113103)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-127-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
    detail.hit.zdb_id: 1501252-9
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  • 7
    Online Resource
    Online Resource
    Pyruvate Kinase Controls Signal Strength in the Insulin Secretory Pathway
    Elsevier BV ; 2020
    In:  Cell Metabolism Vol. 32, No. 5 ( 2020-11), p. 736-750.e5
    Details
    In: Cell Metabolism, Elsevier BV, Vol. 32, No. 5 ( 2020-11), p. 736-750.e5
    Type of Medium: Online Resource
    ISSN: 1550-4131
    URL: Article
    DOI: 10.1016/j.cmet.2020.10.007
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2174469-5
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    β-cell deletion of the PKm1 and PKm2 isoforms of pyruvate kinase in mice reveals their essential role as nutrient sensors for the KATP channel
    eLife Sciences Publications, Ltd ; 2022
    In:  eLife Vol. 11 ( 2022-08-23)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 11 ( 2022-08-23)
    Abstract: Pyruvate kinase (PK) and the phosphoenolpyruvate (PEP) cycle play key roles in nutrient-stimulated K ATP channel closure and insulin secretion. To identify the PK isoforms involved, we generated mice lacking β-cell PKm1, PKm2, and mitochondrial PEP carboxykinase (PCK2) that generates mitochondrial PEP. Glucose metabolism was found to generate both glycolytic and mitochondrially derived PEP, which triggers K ATP closure through local PKm1 and PKm2 signaling at the plasma membrane. Amino acids, which generate mitochondrial PEP without producing glycolytic fructose 1,6-bisphosphate to allosterically activate PKm2, signal through PKm1 to raise ATP/ADP, close K ATP channels, and stimulate insulin secretion. Raising cytosolic ATP/ADP with amino acids is insufficient to close K ATP channels in the absence of PK activity or PCK2, indicating that K ATP channels are primarily regulated by PEP that provides ATP via plasma membrane-associated PK, rather than mitochondrially derived ATP. Following membrane depolarization, the PEP cycle is involved in an ‘off-switch’ that facilitates K ATP channel reopening and Ca 2+ extrusion, as shown by PK activation experiments and β-cell PCK2 deletion, which prolongs Ca 2+ oscillations and increases insulin secretion. In conclusion, the differential response of PKm1 and PKm2 to the glycolytic and mitochondrial sources of PEP influences the β-cell nutrient response, and controls the oscillatory cycle regulating insulin secretion.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.79422
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2022
    detail.hit.zdb_id: 2687154-3
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  • 9
    Online Resource
    Online Resource
    Pyruvate Kinase Controls Signal Strength in the Insulin Secretory Pathway
    Elsevier BV ; 2020
    In:  SSRN Electronic Journal
    Details
    In: SSRN Electronic Journal, Elsevier BV
    Type of Medium: Online Resource
    ISSN: 1556-5068
    URL: Article
    DOI: 10.2139/ssrn.3520952
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
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  • 10
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    Online Resource
    The Retinoblastoma Tumor Suppressor Promotes Efficient Human Cytomegalovirus Lytic Replication
    American Society for Microbiology ; 2015
    In:  Journal of Virology Vol. 89, No. 9 ( 2015-05), p. 5012-5021
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 89, No. 9 ( 2015-05), p. 5012-5021
    Abstract: The retinoblastoma (Rb) tumor suppressor controls cell cycle, DNA damage, apoptotic, and metabolic pathways. DNA tumor virus oncoproteins reduce Rb function by either inducing Rb degradation or physically disrupting complexes between Rb and its myriad binding proteins. Human cytomegalovirus (HCMV), a betaherpesvirus being investigated for potential roles in human cancers, encodes multiple lytic-phase proteins that inactivate Rb in distinct ways, leading to the hypothesis that reduced Rb levels and/or activity would benefit HCMV lytic infection. Paradoxically, we found that Rb knockdown prior to infection, whether transient or constitutive, impaired HCMV lytic infection at multiple stages, notably viral DNA replication, late protein expression, and infectious virion production. The existence of differentially modified forms of Rb, the temporally and functionally distinct means by which HCMV proteins interact with Rb, and the necessity of Rb for efficient HCMV lytic replication combine to highlight the complex relationship between the virus and this critical tumor suppressor. IMPORTANCE Initial work examining viral protein modulation of cell cycle progression and oncogenic transformation revealed that these proteins inactivated the function of cellular tumor suppressor proteins. However, subsequent work, including experiments described here using human cytomegalovirus, demonstrate a more nuanced interaction that includes the necessity of cellular tumor suppressors for efficient viral replication. Understanding the positive impacts that cellular tumor suppressors have on viral infections may reveal new activities of these well-studied yet incompletely understood proteins. The basis for oncolytic viral therapy is the selective replication of viruses in transformed cells in which tumor suppressor function may be compromised. Understanding how tumor suppressors support viral infections may allow for the generation of modified oncolytic viruses with greater selective tumor cell replication and killing.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.00175-15
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2015
    detail.hit.zdb_id: 1495529-5
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