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Article ; Online: Optimizing Axillary Management in Clinical T1-2N0 Mastectomy Patients with Positive Sentinel Lymph Nodes.

Kantor, Olga / Means, Jessica / Grossmith, Samantha / Dey, Tanujit / Bellon, Jennifer R / Mittendorf, Elizabeth A / King, Tari A

Annals of surgical oncology

2021 Volume 29, Issue 2, Page(s) 972–980

Abstract: Background: Following publication of the AMAROS trial, we sought to optimize axillary lymph node dissection (ALND) or postmastectomy radiation therapy (PMRT) + axillary radiation (AxRT) utilization in cT1-2N0 patients with 1-2 positive sentinel lymph ... ...

Abstract	Background: Following publication of the AMAROS trial, we sought to optimize axillary lymph node dissection (ALND) or postmastectomy radiation therapy (PMRT) + axillary radiation (AxRT) utilization in cT1-2N0 patients with 1-2 positive sentinel lymph nodes (SLNs) after mastectomy. Methods: In November 2015, our multidisciplinary group implemented a protocol to omit intraoperative SLN evaluation for mastectomy patients with cT1-2N0 breast cancer likely to be recommended PMRT if found to have 1-2 positive SLNs (age ≤ 60 years and/or high-risk features defined as estrogen receptor-negative and/or positive for lymphovascular invasion). We prospectively evaluated axillary management, short-term complications, and oncologic outcomes in patients with 1-2 positive SLNs. Results: From November 2015 to December 2018, 479 of 560 (85%) cT1-2N0 breast cancers treated with mastectomy were potential candidates for PMRT. Intraoperative SLN evaluation was omitted in 344 (72%), thus following the protocol. Overall, 121 cases had 1-2 positive SLNs: 17 (14%) were managed with observation, 5 (4%) PMRT alone, 59 (49%) PMRT + AxRT, 16 (13%) ALND alone, and 24 (20%) ALND + PMRT. Protocol compliance resulted in less ALND (8% vs. 24%) and less ALND + PMRT (9% vs. 41%, p < 0.01). At median follow-up of 24 months, there was one regional and four distant recurrences, with no regional recurrences or differences in disease-free survival in patients treated with ALND versus PMRT + AxRT (100% vs. 98%, p = 0.67). Similarly, there were no differences in complication rates (p = 0.18). Conclusions: Omitting intraoperative SLN evaluation in cT1-2N0 mastectomy patients who would be candidates for PMRT if found to have positive nodes decreased rates of ALND and minimized use of ALND + PMRT without compromising outcomes.
MeSH term(s)	Axilla ; Breast Neoplasms/surgery ; Female ; Humans ; Lymph Node Excision ; Lymph Nodes/surgery ; Lymphatic Metastasis ; Mastectomy ; Middle Aged ; Sentinel Lymph Node/surgery ; Sentinel Lymph Node Biopsy
Language	English
Publishing date	2021-09-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1200469-8
ISSN	1534-4681 ; 1068-9265
ISSN (online)	1534-4681
ISSN	1068-9265
DOI	10.1245/s10434-021-10726-3
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Article: Effects of harvest season on carcass characteristics of lambs in the Intermountain West

Whaley, J.R. / Murphy, T.W. / Gifford, C.L. / Means, W.J. / Ritten, J.P. / McKibben, H.N. / Page, C.M. / Stewart, W.C.

Applied animal science. 2022 Oct., v. 38, no. 5

2022

Abstract: The objectives of this study were to survey characteristics including hot carcass weight (HCW), 12th rib fat thickness (RFT), body-wall thickness (BWT), longissimus muscle area (LMA), USDA yield grade (USDA YG), percentage closely trimmed retail cuts (RC) ...

Abstract	The objectives of this study were to survey characteristics including hot carcass weight (HCW), 12th rib fat thickness (RFT), body-wall thickness (BWT), longissimus muscle area (LMA), USDA yield grade (USDA YG), percentage closely trimmed retail cuts (RC), and calculated yield grade (Calc YG) of lamb carcasses in the Intermountain West to determine the effects of season of slaughter and interrelationships among carcass characteristics. Lamb carcass characteristics were evaluated in 2 commercial Intermountain West processing plants over one year (n = 10,027). Carcasses were evaluated by season: spring (December–April, n = 2,322) and summer (May–August, n = 7,705). Carcasses of lambs slaughtered in the spring had 3.4 kg heavier HCW (P = 0.04) than those slaughtered in the summer. Subcutaneous fat (RFT; P = 0.06) and Calc YG (P = 0.09) tended to be greater in the spring than summer. Correlation coefficients and models of fit with a linear covariate of HCW indicated negative relationship between HCW and RC and positive relationship with all other carcass traits (P < 0.001). Overall, graded lamb carcasses exceeded commercial processing plant preferred HCW (38.6 kg) by 5% (mean = 40.5 kg) and industry acceptable RFT (6 mm) by 25% (mean = 8.03 mm). Furthermore, 70% of lamb carcasses exceed 6 mm RFT. Season of slaughter contributed to differences in HCW and USDA YG but no other carcass characteristics. Still, carcass data surveyed from the largest lamb-producing region of the United States suggests that the degree of fatness exceeds industry preferences. Although abattoirs mitigate adverse effects of excessive fat through trimming and diverse market outlets, industry-wide efforts that agree on acceptable standards of trimness are needed. Transparent dialog across industry segments should be prioritized in addition to consistent integration of value-based pricing to reduce the proportion of excessively finished lambs.
Keywords	USDA ; carcass weight ; fat thickness ; harvest date ; industry ; longissimus muscle ; markets ; ovine carcasses ; slaughter ; spring ; subcutaneous fat ; summer ; Intermountain West region
Language	English
Dates of publication	2022-10
Size	p. 393-401.
Publishing place	Elsevier Inc.
Document type	Article
ISSN	2590-2865
DOI	10.15232/aas.2022-02322
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Article ; Online: Research Resource: Roles for Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) in Systems Metabolism.

Marcelo, Kathrina L / Ribar, Thomas / Means, Christopher R / Tsimelzon, Anna / Stevens, Robert D / Ilkayeva, Olga / Bain, James R / Hilsenbeck, Susan G / Newgard, Christopher B / Means, Anthony R / York, Brian

Molecular endocrinology (Baltimore, Md.)

2016 Volume 30, Issue 5, Page(s) 557–572

Abstract: A number of epidemiological studies have implicated calcium (Ca(2+)) signaling as a major factor in obesity that contributes to aberrant systems metabolism. Somewhat paradoxically, obesity correlates with decreased circulating Ca(2+) levels, leading to ... ...

Abstract	A number of epidemiological studies have implicated calcium (Ca(2+)) signaling as a major factor in obesity that contributes to aberrant systems metabolism. Somewhat paradoxically, obesity correlates with decreased circulating Ca(2+) levels, leading to increased release of intracellular Ca(2+) stores from the endoplasmic reticulum. These findings suggest that insulin resistance associated with the obese state is linked to activation of canonical Ca(2+) signaling pathways. Mechanistically, increased intracellular Ca(2+) binds calmodulin (CaM) to activate a set of Ca(2+)/CaM-dependent protein kinases. In this research resource, we explore the metabolic functions and implications of Ca(2+)/CaM-dependent protein kinase kinase 2 (CaMKK2) as a metabolic effector of Ca(2+)/CaM action. We reveal the importance of CaMKK2 for gating insulin release from pancreatic β-cells while concomitantly influencing the sensitivity of insulin-responsive tissues. To provide a better understanding of the metabolic impact of CaMKK2 loss, we performed targeted metabolomic analyses of key metabolic byproducts of glucose, fatty acid, and amino acid metabolism in mice null for CaMKK2. We quantified amino acids and acyl carnitines in 3 insulin-sensitive tissues (liver, skeletal muscle, plasma) isolated from CaMKK2(-/-) mice and their wild-type littermates under conditions of dietary stress (low-fat diet, normal chow, high-fat diet, and fasting), thereby unveiling unique metabolic functions of CaMKK2. Our findings highlight CaMKK2 as a molecular rheostat for insulin action and emphasize the importance of Ca(2+)/CaM/CaMKK2 in regulation of whole-body metabolism. These findings reveal that CaMKK2 may be an attractive therapeutic target for combatting comorbidities associated with perturbed insulin signaling.
Language	English
Publishing date	2016-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	639167-9
ISSN	1944-9917 ; 0888-8809
ISSN (online)	1944-9917
ISSN	0888-8809
DOI	10.1210/me.2016-1021
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Article ; Online: Laparoscopic distal pancreatectomy with splenic preservation.

Pryor, A / Means, J R / Pappas, T N

Surgical endoscopy

2007 Volume 21, Issue 12, Page(s) 2326–2330

Abstract: Background: The technique of distal pancreatectomy has been well described, both with en bloc resection of the spleen and with splenic preservation. Splenic preservation during pancreatic tail resection is desirable when oncologically appropriate, yet ... ...

Abstract	Background: The technique of distal pancreatectomy has been well described, both with en bloc resection of the spleen and with splenic preservation. Splenic preservation during pancreatic tail resection is desirable when oncologically appropriate, yet it is technically challenging, particularly with laparoscopic approaches. Skeletonization of the splenic artery and vein is associated with longer operative times and greater potential for bleeding. The authors report their experience with splenic preservation during laparoscopic pancreatic resection using ligation of the splenic vessels and preservation of the short gastric vessels. Methods: A retrospective chart review was performed for all patients who underwent attempted laparoscopic pancreatic resection at Duke University Medical Center from July 2002 to October 2005. Charts were analyzed for demographic information, length of hospital stay, conversion, splenic preservation, and postoperative complications. Results: A total of 12 laparoscopic distal pancreatic resections were attempted for three men and nine women with a mean age was 55.8 years (range, 33-74 years). All 12 patients underwent distal pancreatectomy, 8 with splenic preservation. The spleen was removed from three patients using splenic hilar lesions that prevented splenic salvage. One patient required splenectomy secondary to more than 50% ischemia of the spleen. No patients with preoperatively diagnosed malignancy underwent splenic salvage. The final pathologic diagnosis included neuroendocrine tumors (n = 2), cystic serous (n = 4) and mucinous (n = 2) neoplasms, intraductal papillary mucinous neoplasm (IPMN) (n = 1), pancreatitis (n = 2), and adenocarcinoma (n = 1). Two patients underwent conversion to open surgery for thickened parenchyma secondary to chronic pancreatitis (17%). There were no other conversions. There were three chemical leaks (25%) diagnosed by elevated drain amylase and low volume output, which were managed with intraoperatively placed drains removed at the initial postoperative clinic visit. There were three higher volume leaks (25%) that required extended or percutaneous drainage, with eventual removal. The average blood loss was 215 ml (range, 50-700 ml). The average operative time was 3 h and 41 min (range, 2 h 15 min to 5 h 58 min). The average length of hospital stay was 4 days (range, 2-7 days). Conclusion: Splenic preservation should be performed when technically possible to decrease the morbidity of laparoscopic distal pancreatectomy. The choice to ligate the splenic vessels allows for shorter operative times with minimal perioperative morbidity and blood loss while maintaining the spleen.
MeSH term(s)	Adult ; Aged ; Female ; Humans ; Ischemia/surgery ; Laparoscopy ; Ligation ; Male ; Middle Aged ; Pancreatectomy/adverse effects ; Pancreatectomy/methods ; Pancreatic Diseases/surgery ; Retrospective Studies ; Spleen/blood supply ; Splenectomy ; Stomach/blood supply
Language	English
Publishing date	2007-12
Publishing country	Germany
Document type	Journal Article
ZDB-ID	639039-0
ISSN	1432-2218 ; 0930-2794
ISSN (online)	1432-2218
ISSN	0930-2794
DOI	10.1007/s00464-007-9403-9
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Article ; Online: Single-Cell Transcriptomics Reveals a Conserved Metaplasia Program in Pancreatic Injury.

Ma, Zhibo / Lytle, Nikki K / Chen, Bob / Jyotsana, Nidhi / Novak, Sammy Weiser / Cho, Charles J / Caplan, Leah / Ben-Levy, Olivia / Neininger, Abigail C / Burnette, Dylan T / Trinh, Vincent Q / Tan, Marcus C B / Patterson, Emilee A / Arrojo E Drigo, Rafael / Giraddi, Rajshekhar R / Ramos, Cynthia / Means, Anna L / Matsumoto, Ichiro / Manor, Uri /

Mills, Jason C / Goldenring, James R / Lau, Ken S / Wahl, Geoffrey M / DelGiorno, Kathleen E

Gastroenterology

2021 Volume 162, Issue 2, Page(s) 604–620.e20

Abstract: Background & aims: Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from ADM, the associated ... ...

Abstract	Background & aims: Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from ADM, the associated transcriptional changes, and markers of disease progression. Methods: Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate post-injury. Transcripts of more than 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Developmental trajectories were generated. Data were compared with gastric metaplasia, Kras Results: scRNA-seq of ADM revealed emergence of a mucin/ductal population resembling gastric pyloric metaplasia. Lineage trajectories suggest that some pyloric metaplasia cells can generate tuft and enteroendocrine cells (EECs). Comparison with Kras Conclusions: Under conditions of chronic injury, acinar cells undergo a pyloric-type metaplasia to mucinous progenitor-like populations, which seed disparate tuft cell and EEC lineages. ADM-derived EEC subtypes are diverse. Kras
MeSH term(s)	Acinar Cells/cytology ; Acinar Cells/metabolism ; Carcinoma, Pancreatic Ductal/genetics ; Cell Plasticity/genetics ; Enteroendocrine Cells/cytology ; Enteroendocrine Cells/metabolism ; Gene Expression Profiling ; Humans ; Metaplasia/genetics ; Metaplasia/metabolism ; Mucin 5AC/genetics ; Pancreas/cytology ; Pancreas/metabolism ; Pancreatic Ducts/cytology ; Pancreatic Ducts/metabolism ; Pancreatic Neoplasms/genetics ; Pancreatitis/genetics ; Pancreatitis/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics ; Single-Cell Analysis
Chemical Substances	KRAS protein, human ; MUC5AC protein, human ; Mucin 5AC ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2021-10-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2021.10.027
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Article ; Online: Early dispersal of domestic horses into the Great Plains and northern Rockies.

Taylor, William Timothy Treal / Librado, Pablo / American Horse, Chief Joseph / Shield Chief Gover, Carlton / Arterberry, Jimmy / Afraid of Bear-Cook, Antonia Loretta / Left Heron, Harold / Yellow Hair, Robert Milo / Gonzalez, Mario / Means, Bill / High Crane, Sam / Yellow Bull, Wendell W. / Dull Knife, Barbara / Afraid of Bear, Anita / Tecumseh Collin, Cruz / Ward, Chance / Pasqual, Theresa A / Chauvey, Lorelei / Tonasso-Calviere, Laure /

Schiavinato, Stéphanie / Seguin-Orlando, Andaine / Fages, Antoine / Khan, Naveed / Der Sarkissian, Clio / Liu, Xuexue / Wagner, Stefanie / Leonard, Beth Ginondidoy / Manzano, Bruce L / O'Malley, Nancy / Leonard, Jennifer A / Bernáldez-Sánchez, Eloísa / Barrey, Eric / Charliquart, Léa / Robbe, Emilie / Denoblet, Thibault / Gregersen, Kristian / Vershinina, Alisa O / Weinstock, Jaco / Rajić Šikanjić, Petra / Mashkour, Marjan / Shingiray, Irina / Aury, Jean-Marc / Perdereau, Aude / Alquraishi, Saleh / Alfarhan, Ahmed H / Al-Rasheid, Khaled A S / Trbojević Vukičević, Tajana / Buric, Marcel / Sauer, Eberhard / Lucas, Mary / Brenner-Coltrain, Joan / Bozell, John R / Thornhill, Cassidee A / Monagle, Victoria / Perri, Angela / Newton, Cody / Hall, W Eugene / Conver, Joshua L / Le Roux, Petrus / Buckser, Sasha G / Gabe, Caroline / Belardi, Juan Bautista / Barrón-Ortiz, Christina I / Hart, Isaac A / Ryder, Christina / Sponheimer, Matthew / Shapiro, Beth / Southon, John / Hibbs, Joss / Faulkner, Charlotte / Outram, Alan / Patterson Rosa, Laura / Palermo, Katelyn / Solé, Marina / William, Alice / McCrory, Wayne / Lindgren, Gabriella / Brooks, Samantha / Eché, Camille / Donnadieu, Cécile / Bouchez, Olivier / Wincker, Patrick / Hodgins, Gregory / Trabert, Sarah / Bethke, Brandi / Roberts, Patrick / Jones, Emily Lena / Running Horse Collin, Yvette / Orlando, Ludovic

Science (New York, N.Y.)

2023 Volume 379, Issue 6639, Page(s) 1316–1323

Abstract: The horse is central to many Indigenous cultures across the American Southwest and the Great Plains. However, when and how horses were first integrated into Indigenous lifeways remain contentious, with extant models derived largely from colonial records. ...

Abstract	The horse is central to many Indigenous cultures across the American Southwest and the Great Plains. However, when and how horses were first integrated into Indigenous lifeways remain contentious, with extant models derived largely from colonial records. We conducted an interdisciplinary study of an assemblage of historic archaeological horse remains, integrating genomic, isotopic, radiocarbon, and paleopathological evidence. Archaeological and modern North American horses show strong Iberian genetic affinities, with later influx from British sources, but no Viking proximity. Horses rapidly spread from the south into the northern Rockies and central plains by the first half of the 17th century CE, likely through Indigenous exchange networks. They were deeply integrated into Indigenous societies before the arrival of 18th-century European observers, as reflected in herd management, ceremonial practices, and culture.
MeSH term(s)	Animals ; Humans ; Archaeology ; Horses ; United States ; Domestication ; Animals, Domestic
Language	English
Publishing date	2023-03-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.adc9691
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Article ; Online: Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated Cancer.

Means, Anna L / Freeman, Tanner J / Zhu, Jing / Woodbury, Luke G / Marincola-Smith, Paula / Wu, Chao / Meyer, Anne R / Weaver, Connie J / Padmanabhan, Chandrasekhar / An, Hanbing / Zi, Jinghuan / Wessinger, Bronson C / Chaturvedi, Rupesh / Brown, Tasia D / Deane, Natasha G / Coffey, Robert J / Wilson, Keith T / Smith, J Joshua / Sawyers, Charles L /

Goldenring, James R / Novitskiy, Sergey V / Washington, M Kay / Shi, Chanjuan / Beauchamp, R Daniel

Cellular and molecular gastroenterology and hepatology

2018 Volume 6, Issue 3, Page(s) 257–276

Abstract: Background & aims: Chronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in ... ...

Abstract	Background & aims: Chronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in epithelial cells, is critical for developing therapeutic interventions. Here, we explored the roles of transforming growth factor β (TGFβ) family signaling through SMAD4 in colonic epithelial cells. Methods: The Results: Dextran sodium sulfate treatment was sufficient to drive carcinogenesis in mice lacking colonic Conclusions: TGFβ suppresses the expression of proinflammatory genes in the colon epithelium, and loss of its downstream mediator, SMAD4, is sufficient to initiate inflammation-driven colon cancer. Transcript profiling: GSE100082.
MeSH term(s)	Animals ; Bone Morphogenetic Protein 2/genetics ; Bone Morphogenetic Protein 2/metabolism ; Carcinoma/etiology ; Carcinoma/immunology ; Carcinoma/pathology ; Cell Line ; Cell Line, Tumor ; Colitis/chemically induced ; Colitis/complications ; Colitis/immunology ; Colorectal Neoplasms/etiology ; Colorectal Neoplasms/immunology ; Colorectal Neoplasms/pathology ; Dextran Sulfate/pharmacology ; Humans ; Inflammation/chemically induced ; Inflammation/complications ; Inflammation/immunology ; Intestinal Mucosa/drug effects ; Intestinal Mucosa/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Smad4 Protein/genetics ; Smad4 Protein/immunology ; Transforming Growth Factor beta1/genetics ; Transforming Growth Factor beta1/metabolism
Chemical Substances	Bmp2 protein, mouse ; Bone Morphogenetic Protein 2 ; Smad4 Protein ; Smad4 protein, mouse ; Transforming Growth Factor beta1 ; Dextran Sulfate (9042-14-2)
Language	English
Publishing date	2018-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2819778-1
ISSN	2352-345X ; 2352-345X
ISSN (online)	2352-345X
ISSN	2352-345X
DOI	10.1016/j.jcmgh.2018.05.006
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Article: Inhibition of human erythroid colony-forming units by tumor necrosis factor requires beta interferon.

Means, R T / Krantz, S B

The Journal of clinical investigation

1993 Volume 91, Issue 2, Page(s) 416–419

Abstract: ... accessory cells which are predominantly stromal elements (Means, R. T., Jr., E. N. Dessypris, and S. B ...

Abstract	We have previously reported that inhibition of human CFU-erythroid (E) colony formation by tumor necrosis factor (TNF) is an indirect effect mediated by a soluble factor released from a fraction of marrow accessory cells which are predominantly stromal elements (Means, R. T., Jr., E. N. Dessypris, and S. B. Krantz. 1990. J. Clin. Invest. 86:538-541). Further studies reported here identify a mediator of this effect. The inhibitory effect of recombinant TNF on marrow CFU-E is ablated by neutralizing antibodies to human beta IFN, but not by antibodies to gamma IFN or IL-1. Anti-beta IFN also neutralizes the inhibitory effect of conditioned medium prepared from marrow cells exposed to TNF. Human beta IFN inhibits colony formation by unpurified marrow CFU-E as well as highly purified CFU-E generated from peripheral blood progenitors, and limiting dilution analysis shows that this is a direct inhibitory effect. TNF has been implicated in the pathogenesis of the anemia of chronic diseases since blood TNF levels are elevated in many patients with this syndrome, and since exposure to TNF produces a similar anemia in either humans or mice. The present study demonstrates that beta IFN is a required mediator of this inhibitory effect on erythropoiesis.
MeSH term(s)	Erythroid Precursor Cells/drug effects ; Erythropoiesis/drug effects ; Humans ; In Vitro Techniques ; Interferon-beta/pharmacology ; Recombinant Proteins/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology
Chemical Substances	Recombinant Proteins ; Tumor Necrosis Factor-alpha ; Interferon-beta (77238-31-4)
Language	English
Publishing date	1993-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI116216
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Article: A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells.

Yeh, Elizabeth / Cunningham, Melissa / Arnold, Hugh / Chasse, Dawn / Monteith, Teresa / Ivaldi, Giovanni / Hahn, William C / Stukenberg, P Todd / Shenolikar, Shirish / Uchida, Takafumi / Counter, Christopher M / Nevins, Joseph R / Means, Anthony R / Sears, Rosalie

Nature cell biology

2004 Volume 6, Issue 4, Page(s) 308–318

Abstract: ... replaces SV40 small T antigen in human cell transformation and tumorigenesis assays. Therefore, small T ...

Abstract	The stability of c-Myc is regulated by multiple Ras effector pathways. Phosphorylation at Ser 62 stabilizes c-Myc, whereas subsequent phosphorylation at Thr 58 is required for its degradation. Here we show that Ser 62 is dephosphorylated by protein phosphatase 2A (PP2A) before ubiquitination of c-Myc, and that PP2A activity is regulated by the Pin1 prolyl isomerase. Furthermore, the absence of Pin1 or inhibition of PP2A stabilizes c-Myc. A stable c-Myc(T58A) mutant that cannot bind Pin1 or be dephosphorylated by PP2A replaces SV40 small T antigen in human cell transformation and tumorigenesis assays. Therefore, small T antigen, which inactivates PP2A, exerts its oncogenic potential by preventing dephosphorylation of c-Myc, resulting in c-Myc stabilization. Thus, Ras-dependent signalling cascades ensure transient and self-limiting accumulation of c-Myc, disruption of which contributes to human cell oncogenesis.
MeSH term(s)	Amino Acid Sequence/genetics ; Animals ; Antigens, Polyomavirus Transforming/genetics ; Antigens, Polyomavirus Transforming/metabolism ; Cell Line ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Genes, myc/genetics ; Humans ; Mice ; Mutation/genetics ; NIMA-Interacting Peptidylprolyl Isomerase ; Neoplasms/genetics ; Neoplasms/metabolism ; Peptidylprolyl Isomerase/genetics ; Peptidylprolyl Isomerase/metabolism ; Phosphoprotein Phosphatases/antagonists & inhibitors ; Phosphoprotein Phosphatases/genetics ; Phosphoprotein Phosphatases/metabolism ; Phosphorylation ; Protein Phosphatase 2 ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; RNA Stability/genetics ; Rats ; Serine/metabolism ; Signal Transduction/genetics ; Threonine/metabolism
Chemical Substances	Antigens, Polyomavirus Transforming ; NIMA-Interacting Peptidylprolyl Isomerase ; Proto-Oncogene Proteins c-myc ; Threonine (2ZD004190S) ; Serine (452VLY9402) ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; Protein Phosphatase 2 (EC 3.1.3.16) ; PIN1 protein, human (EC 5.2.1.8) ; Peptidylprolyl Isomerase (EC 5.2.1.8) ; Pin1 protein, mouse (EC 5.2.1.8)
Language	English
Publishing date	2004-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/ncb1110
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Article: Localization of calmodulin in rat cerebellum by immunoelectron microscopy.

Lin, C T / Dedman, J R / Brinkley, B R / Means, A R

The Journal of cell biology

1980 Volume 85, Issue 2, Page(s) 473–480

Abstract: Calmodulin, a multifunctional Ca(++)-binding protein, is present in all eucaryotic cells. We have investigated the distribution of this protein in the rat cerebellum by immunoelectron microscopy using a Fab-peroxidase conjugate technique. In Purkinje and ...

Abstract	Calmodulin, a multifunctional Ca(++)-binding protein, is present in all eucaryotic cells. We have investigated the distribution of this protein in the rat cerebellum by immunoelectron microscopy using a Fab-peroxidase conjugate technique. In Purkinje and granular cell bodies, calmodulin reaction product was found localized both on free ribosomes and on those attached to rough endoplasmic reticulum (RER) and the nuclear envelope. No calmoduline was observed in the cisternae of RER or the Golgi apparactus. Calmodulin did not appear to be concentrated in the soluble fraction of the cell under the conditions used. Rather, peroxidase reaction product could be seen associated with membranes of the Golgi apparatus the smooth endoplasmic reticulum (SER), and the plasma membrane of both cell bodies and neuronal processes. In the neuronal dendrites, calmodulin appeared to be concentrated on membranes of the SER, small vesicles, and mitochondria. Also, granular calmodulin was observed in the amorphous material. In the synaptic junction, a large amount of calmodulin was seen attached to the inner surface of the postsynaptic membrane, whereas very little was observed in the presynaptic membrane or vesicles. These observations suggest that calmodulin is synthesized on ribosomes and discharged into the cytosol, and that it then becomes associated with a variety of intracellular membranes. Calmodulin also seems to be transported via neuronal processes to the postsynaptic membrane. Calmodulin localization at the postsynaptic membrane suggests that this protein may mediate calcium effects at the synaptic junction and, thus, may play a role in the regulation of neurotransmission.
MeSH term(s)	Animals ; Calcium-Binding Proteins/analysis ; Calmodulin/analysis ; Cerebellum/analysis ; Cerebellum/ultrastructure ; Dendrites/analysis ; Immunoenzyme Techniques ; Microscopy, Electron ; Organoids/analysis ; Purkinje Cells/analysis ; Purkinje Cells/ultrastructure ; Rats ; Synaptic Membranes/analysis
Chemical Substances	Calcium-Binding Proteins ; Calmodulin
Language	English
Publishing date	1980-05
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.85.2.473
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