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Ken C. Walls

University of California, Irvine

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Kevin A. Roth

Columbia University

Paul J. Goodfellow

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

David G. Mutch

Washington University in St. Louis

Israel Zighelboim

St. Luke's University Health Network

Mary A. Mallon

Washington University in St. Louis

Barbara J. Klocke

University of Alabama at Birmingham

Pearlly S. Yan

The Ohio State University

Amy P. Schmidt

Washington University in St. Louis

Matthew A. Powell

Washington University in St. Louis

Tim H.‐M. Huang

The University of Texas Health Science Center at San Antonio

Cooperative Institutions

University of California, Irvine

University of Alabama at Birmingham

Washington University in St. Louis

UC Irvine Health

Johns Hopkins University

Instituto de Investigación Biomédica de Málaga

Universidad de Málaga

Biomedical Research Networking Center on Neurodegenerative Diseases

Gynecologic Oncology Group

The Ohio State University

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Data from Differential Methylation Hybridization Array of Endometrial Cancers Reveals Two Novel Cancer-Specific Methylation Markers

Israel Zighelboim Paul J. Goodfellow Amy P. Schmidt Ken C. Walls Mary A. Mallon

<div>Abstract<p><b>Purpose:</b> To identify novel endometrial cancer-specific methylation markers and to determine their association with clinicopathologic variables and survival outcomes.</p><p><b>Experimental Design:</b> Differential methylation hybridization analysis (DMH) was done for 20 endometrioid endometrial cancers using normal endometrial DNA as a reference control. Combined bisulfite restriction analysis (COBRA) was used to verify methylation of sequences identified by DMH. Bisulfite sequencing was undertaken to further define CpG island methylation and to confirm the reliability of the COBRA. The methylation status of newly identified markers and the <i>MLH1</i> promoter was evaluated by COBRA in a large series of endometrioid (<i>n</i> = 361) and non-endometrioid uterine cancers (<i>n</i> = 23).</p><p><b>Results:</b> DMH and COBRA identified two CpG islands methylated in tumors but not in normal DNAs: <i>SESN3</i> (PY2B4) and <i>TITF1</i> (SC77F6/154). Bisulfite sequencing showed dense methylation of the CpG islands and confirmed the COBRA assays. <i>SESN3</i> and <i>TITF1</i> were methylated in 20% and 70% of endometrioid tumors, respectively. <i>MLH1</i> methylation was seen in 28% of the tumors. <i>TITF1</i> and <i>SESN3</i> methylation was highly associated with <i>MLH1</i> methylation (<i>P</i> < 0.0001). <i>SESN3</i> and <i>TITF1</i> were methylated in endometrioid and non-endometrioid tumors, whereas <i>MLH1</i> methylation was restricted to endometrioid tumors. Methylation at these markers was not associated with survival outcomes.</p><p><b>Conclusions:</b> The 5′ CpG islands for <i>SESN3</i> and <i>TITF1</i> are novel cancer-specific methylation markers. Methylation at these loci is strongly associated with aberrant <i>MLH1</i> methylation in endometrial cancers. <i>SESN3, TITF1</i> and <i>MLH1</i> methylation did not predict overall survival or disease-free survival in this large cohort of patients with endometrioid endometrial cancer.</p></div>

Bisulfite

Bisulfite sequencing

CpG site

MLH1

Cobra

10.1158/1078-0432.c.6518314.v1

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Lysosomal Dysfunction Promotes Autophagic Stress and NPC Death

The FASEB Journal (2008)

Ken C. Walls Jianhua Zhang Ying Geng Kevin A. Roth

Autophagic pathways have been shown to regulate neural precursor cell (NPC) survival during nervous system development. To determine whether lysosomal dysfunction leads to increased autophagic vacuoles (AVs) and NPC death, we treated mouse cerebellar neural stem cells (C17.2 cell line) and FGF2‐expanded primary cerebellar NPCs with lysosomal dysfunction inducing agents chloroquine (CQ), bafilomycin A1 (Baf A1), and ammonium chloride (NH4Cl). CQ, NH4Cl, and Baf A1 treated NPCs underwent apoptosis, as evidenced by cytological features and cleaved caspase‐3 immunoreactivity. In comparison to wild‐type NPCs, Bax‐deficient NPCs exhibited significantly less caspase‐3 activation and cell death in response to lysosomal dysfunction inducing agents. These agents also produced increased levels of autophagy‐associated proteins LC3‐II and Beclin1. Cycloheximide, a protein synthesis inhibitor, attenuated AV formation in response to CQ as evidenced by decreased LC3‐II. However, cycloheximide had no effect on caspase‐3 activation or cell death indicating that AV accumulation is not necessary for CQ‐induced NPC death. p53‐deficient NPCs showed significant protection from CQ‐induced death compared to wild‐type NPCs. In total, our data demonstrate that lysosomal dysfunction leads to AV accumulation as well as p53‐ and Bax‐ dependent NPC death.

Bafilomycin

10.1096/fasebj.22.1_supplement.1121.10

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Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity

Molecular Brain (2008)

Liyan Qiao Shusei Hamamichi Kim A. Caldwell Guy A. Caldwell Talene A. Yacoubian

Abstract α-synuclein (α-syn) is a main component of Lewy bodies (LB) that occur in many neurodegenerative diseases, including Parkinson's disease (PD), dementia with LB (DLB) and multi-system atrophy. α-syn mutations or amplifications are responsible for a subset of autosomal dominant familial PD cases, and overexpression causes neurodegeneration and motor disturbances in animals. To investigate mechanisms for α-syn accumulation and toxicity, we studied a mouse model of lysosomal enzyme cathepsin D (CD) deficiency, and found extensive accumulation of endogenous α-syn in neurons without overabundance of α-syn mRNA. In addition to impaired macroautophagy, CD deficiency reduced proteasome activity, suggesting an essential role for lysosomal CD function in regulating multiple proteolytic pathways that are important for α-syn metabolism. Conversely, CD overexpression reduces α-syn aggregation and is neuroprotective against α-syn overexpression-induced cell death in vitro. In a C. elegans model, CD deficiency exacerbates α-syn accumulation while its overexpression is protective against α-syn-induced dopaminergic neurodegeneration. Mutated CD with diminished enzymatic activity or overexpression of cathepsins B (CB) or L (CL) is not protective in the worm model, indicating a unique requirement for enzymatically active CD. Our data identify a conserved CD function in α-syn degradation and identify CD as a novel target for LB disease therapeutics.

Synucleinopathies

10.1186/1756-6606-1-17

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Citations (241)

Supplementary Table S1 from Differential Methylation Hybridization Array of Endometrial Cancers Reveals Two Novel Cancer-Specific Methylation Markers

Israel Zighelboim Paul J. Goodfellow Amy P. Schmidt Ken C. Walls Mary A. Mallon

Supplementary Table S1 from Differential Methylation Hybridization Array of Endometrial Cancers Reveals Two Novel Cancer-Specific Methylation Markers

Table (database)

10.1158/1078-0432.22441177

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Citations (0)

p-Tau immunotherapy reduces soluble and insoluble tau in aged 3xTg-AD mice

Neuroscience Letters (2014)

Ken C. Walls Rahasson R. Ager Vitaly Vasilevko David Cheng Rodrigo Medeiros

Tau Pathology

Tau protein

10.1016/j.neulet.2014.05.047

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Citations (54)

Data from Differential Methylation Hybridization Array of Endometrial Cancers Reveals Two Novel Cancer-Specific Methylation Markers

Israel Zighelboim Paul J. Goodfellow Amy P. Schmidt Ken C. Walls Mary A. Mallon

<div>Abstract<p><b>Purpose:</b> To identify novel endometrial cancer-specific methylation markers and to determine their association with clinicopathologic variables and survival outcomes.</p><p><b>Experimental Design:</b> Differential methylation hybridization analysis (DMH) was done for 20 endometrioid endometrial cancers using normal endometrial DNA as a reference control. Combined bisulfite restriction analysis (COBRA) was used to verify methylation of sequences identified by DMH. Bisulfite sequencing was undertaken to further define CpG island methylation and to confirm the reliability of the COBRA. The methylation status of newly identified markers and the <i>MLH1</i> promoter was evaluated by COBRA in a large series of endometrioid (<i>n</i> = 361) and non-endometrioid uterine cancers (<i>n</i> = 23).</p><p><b>Results:</b> DMH and COBRA identified two CpG islands methylated in tumors but not in normal DNAs: <i>SESN3</i> (PY2B4) and <i>TITF1</i> (SC77F6/154). Bisulfite sequencing showed dense methylation of the CpG islands and confirmed the COBRA assays. <i>SESN3</i> and <i>TITF1</i> were methylated in 20% and 70% of endometrioid tumors, respectively. <i>MLH1</i> methylation was seen in 28% of the tumors. <i>TITF1</i> and <i>SESN3</i> methylation was highly associated with <i>MLH1</i> methylation (<i>P</i> < 0.0001). <i>SESN3</i> and <i>TITF1</i> were methylated in endometrioid and non-endometrioid tumors, whereas <i>MLH1</i> methylation was restricted to endometrioid tumors. Methylation at these markers was not associated with survival outcomes.</p><p><b>Conclusions:</b> The 5′ CpG islands for <i>SESN3</i> and <i>TITF1</i> are novel cancer-specific methylation markers. Methylation at these loci is strongly associated with aberrant <i>MLH1</i> methylation in endometrial cancers. <i>SESN3, TITF1</i> and <i>MLH1</i> methylation did not predict overall survival or disease-free survival in this large cohort of patients with endometrioid endometrial cancer.</p></div>

Bisulfite

Bisulfite sequencing

MLH1

Cobra

CpG site

10.1158/1078-0432.c.6518314

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Citations (0)

Altered Regulation of Phosphatidylinositol 3-kinase Signaling in Cathepsin D-Deficient Brain

Autophagy (2007)

Ken C. Walls Barbara J. Klocke Paul Säftig Masahiro Shibata Yasuo Uchiyama

AbstractCathepsin D (CD) is an essential lysosomal protease and mice lacking this enzyme exhibit neuropathology similar to that observed in brains of patients with neuronal ceroid lipofuscinosces (NCL/Batten disease), a group of autosomal recessive pediatric neurodegenerative diseases. CD-deficient (CD-/-) brains exhibit a dramatic induction of autophagic stress as defined by the aberrant accumulation of autophagosomes, which is concomitant with markers of apoptosis. However, the signaling abnormalities which lead to CD deficiency-induced neurodegeneration are poorly defined. Since phosphatidylinositol-3 kinase (PI3-K) is known to regulate both apoptosis and autophagy, PI3-K-mediated signaling events were assessed in CD-/- brain at P14 and P25-26. Compared to WT littermate controls, CD-/- cortical neurons exhibited a widespread decrease in phosphorylation of Akt (inactivation) and GSK3beta (disinhibition) at P25-26, while levels of total Akt and GSK3beta remained unchanged. This P25-26-specific decrease in phosphorylation of Akt and GSK-3beta in CD-/- brain coincided temporally with markers of apoptosis but followed the induction of autophagic stress observed at both P14 and P25-26. In addition, levels and/or activation of mTOR and Beclin were not affected by CD deficiency, suggesting that the accumulation of autophagosomes is not due to an increased synthesis of autophagosomes but rather from an inhibition of autophagosome recycling, due most likely to a compromise in lysosome function. Together these observations indicate a pronounced decrease in pro-survival PI3-K signaling in CD-/- brain that may contribute to autophagic stress-induced and apoptotic neuropathology.

Sequestosome 1

10.4161/auto.3822

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Citations (36)

Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers

Proceedings of the National Academy of Sciences (2003)

Paul J. Goodfellow Barbara M. Buttin Thomas J. Herzog Janet S. Rader Randall K. Gibb

Endometrial cancer is the most common gynecologic malignancy in the United States and the most frequent extracolonic tumor in hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC patients have inherited defects in DNA mismatch repair and the microsatellite instability (MSI) tumor phenotype. Sporadic endometrial cancers also exhibit MSI, usually associated with methylation of the MLH1 promoter. Germ-line MSH6 mutations, which are rare in HNPCC, have been reported in several families with multiple members affected with endometrial carcinoma. We reasoned that MSH6 mutation might account for loss of mismatch repair in MSI-positive endometrial cancers in which the cause of MSI is unknown. We therefore investigated MSI and MLH1 promoter methylation in 441 endometrial cancer patients unselected for age or personal and family history of cancers. MSI and MLH1 promoter methylation status were associated with age of onset and tumor histology. One hundred cases (23% of the entire series) were evaluated for MSH6 defects. Inactivating germ-line MSH6 mutations were identified in seven women with MSI-positive, MLH1 promoter unmethylated cancers. Most of the MSI in these cases was seen with mononucleotide repeat markers. The MSH6 mutation carriers were significantly younger than the rest of the population (mean age 54.8 versus 64.6, P = 0.04). Somatic mutations were seen in 17 tumors, all of which had MSI. Our data suggest that inherited defects in MSH6 in women with endometrial cancer are relatively common. The minimum estimate of the prevalence of inherited MSH6 mutation in endometrial cancer is 1.6% (7 of 441), comparable with the predicted prevalence for patients with colorectal cancer.

MSH6

MLH1

Microsatellite Instability

Lynch Syndrome

10.1073/pnas.1030231100

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Citations (226)

Presenilin-null cells have altered two-pore calcium channel expression and lysosomal calcium: Implications for lysosomal function

Brain Research (2012)

Kara M. Neely Kayala George D. Dickinson Anet Minassian Ken C. Walls Kim N. Green

Calcium Signaling

TRPV6

Proteolysis

10.1016/j.brainres.2012.10.036

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Citations (48)

Neural Stem Cell Death Regulation in Nervous System Development and Disease

Springer eBooks (2012)

Ken C. Walls Kevin A. Roth

Neural cell

Neural Development

10.1007/978-1-4614-3801-4_7

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Citations (2)