Tumor formation in p53 mutant ovaries transplanted into wild-type female hosts

The germ line exhibits sexual dimorphism as do the somatic tissues. Cells with the 2X;2A chromosome constitution will follow the oogenic pathway and X;2A cells will develop into sperm. In both somatic and germ-line tissues, the sexual pathway chosen by the cells depends on the gene Sex-lethal (Sxl), whose function is continuously needed for female development. In the soma, the sex of the cells is autonomously determined by the X:A signal while, in the germ line, the sex is determined by cell autonomous (the X:A signal) and somatic inductive signals. Three X-linked genes have been identified, scute (sc), sisterless-a (sis-a) and runt (run), that determine the initial functional state of Sxl in the soma. Using pole cell transplantation, we have tested whether these genes are also needed to activate Sxl in the germ line. We found that germ cells simultaneously heterozygous for sc, sis-a, run and a deficiency for Sxl transplanted into wild-type female hosts develop into functional oocytes. We conclude that the genes sc, sis-a and run needed to activate Sxl in the soma seem not to be required to activate this gene in the germ line; therefore, the X:A signal would be made up by different genes in somatic and germ-line tissues. The Sxlf7M1/Sxlfc females do not have developed ovaries. We have shown that germ cells of this genotype transplanted into wild-type female hosts produce functional oocytes. We conclude that the somatic component of the gonads in Sxlf7M1/Sxlfc females is affected, and consequently germ cells do not develop.(ABSTRACT TRUNCATED AT 250 WORDS)

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PDTM-29. STRUCTURE FUNCTION AND CELL TYPE DETERMINANTS OF C11orf95-RELA DRIVEN TUMORS IN MICE

Neuro-Oncology ◽

10.1093/neuonc/noz175.805 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi193-vi193

Author(s):

Jesse Dunnack ◽

Ericka Randazzo ◽

Jahmique Caines ◽

Jame He ◽

Joseph LoTurco

Keyword(s):

Nuclear Localization ◽

Transcriptional Activation ◽

Point Mutations ◽

Cell Types ◽

Tumor Formation ◽

Wild Type ◽

Nuclear Localization Signals ◽

Transcriptional Activation Domain ◽

Neuronal Progenitor ◽

Glial Progenitor

Abstract We used a new mouse model to better understand the cellular and molecular determinants of tumors driven by the C11orf95-RELA fusion. Our approach makes use of in utero electroporation and a binary transposase system to introduce human C11orf95-RELA sequence, wild type and mutant, into neural progenitors, and drive expression of the fusion in different glial and neuronal progenitor cell types. Our results indicate that truncations or point mutations in C11orf95 sequence which interfere with nuclear localization result in a complete loss of tumor-inducing activity. The mutations include truncations of the first 60 amino acids, internal truncations that delete possible mono and bipartite nuclear localization signals, and point mutations of two cysteines and histidines that make up a possible zinc finger domain in C11orf95. Interestingly, all of the mutations that block tumorigenesis also block signal independent nuclear localization of the wild type fusion, without blocking induction of NFKB response genes. We further found that over-expression of the NFKB1 subunit P50 which lacks a transcriptional activation domain significantly inhibits tumor formation by the fusion. In addition, we find that driving expression of the wild type fusion in glial progenitor types using promoters for either astrocytes or oligodendrocytes results in the formation of tumors with transcriptomes displaying significant similarities to human supratentorial ependymoma (ST-EPN), but with distinct patterns depending upon the glial progenitor promoter utilized. In contrast, promoters driving expression selectively in neuron restricted progenitors do not result in the formation of ST-EPN. Together our results reveal three new features of C11orf95-RELA driven tumorigenesis: i) multiple sequences within the C11orf95 domain are required for oncogenic driver activity of the fusion, ii) the P50 subunit of NFKB1 can inhibit fusion induced tumorigenesis, and iii) neuron-restricted precursors are less competent than glia-restricted precursors to form tumors induced by C11orf95-RELA.

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Abstract P2-06-11: Wild type N-Ras, overexpressed in basal-like breast cancer, promotes tumor formation by inducing IL8 secretion via JAK2 activation

10.1158/1538-7445.sabcs15-p2-06-11 ◽

2016 ◽

Author(s):

Z-Y Zheng ◽

W Bu ◽

L Tian ◽

C Fan ◽

X Gao ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Formation ◽

Wild Type ◽

Basal Like Breast Cancer

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Transformation by Polyomavirus Middle T Antigen Involves a Unique Bimodal Interaction with the Hippo Effector YAP

Journal of Virology ◽

10.1128/jvi.00417-16 ◽

2016 ◽

Vol 90 (16) ◽

pp. 7032-7045 ◽

Cited By ~ 10

Author(s):

Cecile Rouleau ◽

Arun T. Pores Fernando ◽

Justin H. Hwang ◽

Nathalie Faure ◽

Tao Jiang ◽

...

Keyword(s):

Transcriptional Activation ◽

T Antigen ◽

Tumor Formation ◽

Ras Signaling ◽

Hippo Signaling ◽

Control Mechanisms ◽

Positive Contribution ◽

Activation Functions ◽

Wild Type ◽

Middle T Antigen

ABSTRACTMurine polyomavirus has repeatedly provided insights into tumorigenesis, revealing key control mechanisms such as tyrosine phosphorylation and phosphoinositide 3-kinase (PI3K) signaling. We recently demonstrated that polyomavirus small T antigen (ST) binds YAP, a major effector of Hippo signaling, to regulate differentiation. Here we characterize YAP as a target of middle T antigen (MT) important for transformation. Through a surface including residues R103 and D182, wild-type MT binds to the YAP WW domains. Mutation of either R103 or D182 of MT abrogates YAP binding without affecting binding to other signaling molecules or the strength of PI3K or Ras signaling. Either genetic abrogation of YAP binding to MT or silencing of YAP via short hairpin RNA (shRNA) reduced MT transformation, suggesting that YAP makes a positive contribution to the transformed phenotype. MT targets YAP both by activating signaling pathways that affect it and by binding to it. MT signaling, whether from wild-type MT or the YAP-binding MT mutant, promoted YAP phosphorylation at S127 and S381/397 (YAP2/YAP1). Consistent with the known functions of these phosphorylated serines, MT signaling leads to the loss of YAP from the nucleus and degradation. Binding of YAP to MT brings it together with protein phosphatase 2A (PP2A), leading to the dephosphorylation of YAP in the MT complex. It also leads to the enrichment of YAP in membranes. Taken together, these results indicate that YAP promotes MT transformation via mechanisms that may depart from YAP's canonical oncogenic transcriptional activation functions.IMPORTANCEThe highly conserved Hippo/YAP pathway is important for tissue development and homeostasis. Increasingly, changes in this pathway are being associated with cancer. Middle T antigen (MT) is the primary polyomavirus oncogene responsible for tumor formation. In this study, we show that MT signaling promotes YAP phosphorylation, loss from the nucleus, and increased turnover. Notably, MT genetics demonstrate that YAP binding to MT is important for transformation. Because MT also binds PP2A, YAP bound to MT is dephosphorylated, stabilized, and localized to membranes. Taken together, these results indicate that YAP promotes MT transformation via mechanisms that depart from YAP's canonical oncogenic transcriptional activation functions.

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NHE2X3 DKO mice exhibit gender-specific NHE8 compensation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00546.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. G647-G653 ◽

Cited By ~ 15

Author(s):

Hua Xu ◽

Jing Li ◽

Rongji Chen ◽

Bo Zhang ◽

Chunhui Wang ◽

...

Keyword(s):

Sodium Absorption ◽

Mrna Synthesis ◽

Wild Type ◽

Double Knockout ◽

Sodium Hydrogen Exchanger ◽

Wild Type Male ◽

Wild Type Female ◽

Important Player ◽

First Time ◽

Gender Specific

NHE8, the newest member of the sodium/hydrogen exchanger family, is expressed in the epithelial cells of the intestine and the kidney. Intestinal expression of NHE8 is significantly higher than that of NHE2 and NHE3 at a young age, suggesting that NHE8 is an important player for intestinal sodium absorption during early development. The current study was designed to explore if NHE8 plays a compensatory role for the loss of NHE2 and NHE3 function in NHE2X3 double-knockout (NHE2X3 DKO) mice. We further explored the regulatory mechanism(s) responsible for the change in NHE8 expression in NHE2X3 DKO mice. We found that >95% of NHE2X3 DKO mice survived through weanling. However, only 60% of male NHE2X3 DKO mice and 88% of female NHE2X3 DKO mice survived to 6 wk of life. We also found that the expression of NHE8 in wild-type female mice was higher compared with wild-type male mice after puberty. In NHE2X3 KDO mice, NHE8 expression was increased in females but not in males. Using Caco-2 cells as a model of the small intestine, we showed that testosterone inhibited endogenous NHE8 expression by reducing NHE8 mRNA synthesis, whereas estrogen had no effect on NHE8 expression. Thus our data show for the first time that intestinal NHE8 has a compensatory role in NHE2X3 DKO mice and this regulation is gender-dependent.

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A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation

Endocrine Related Cancer ◽

10.1530/erc-12-0308 ◽

2013 ◽

Vol 20 (4) ◽

pp. 515-525 ◽

Cited By ~ 19

Author(s):

Cameron M Armstrong ◽

Autumn R Billimek ◽

Kimberly F Allred ◽

Joseph M Sturino ◽

Brad R Weeks ◽

...

Keyword(s):

Colon Cancer ◽

Estrogen Receptor ◽

Epithelial Cells ◽

Postmenopausal Women ◽

Estrogen Replacement Therapy ◽

Tumor Formation ◽

Receptor Expression ◽

Estrogen Replacement ◽

Wild Type ◽

Mrna And Protein Expression

Postmenopausal women on estrogen replacement therapy (ERT) have a reduced risk of developing colon cancer compared with postmenopausal women not on ERT, suggesting a role for estradiol (E2) in protection against this disease. To determine whether E2protects against inflammation-associated colon cancer when administered following the initiation of colonic DNA damage, in this study, we implanted E2-containing pellets into mice after co-treatment with azoxymethane and two rounds of dextran sulfate sodium (DSS). Wild-type (WT) E2-treated mice had reduced numbers and average area of adenocarcinomas compared with the control mice. These effects were lost in estrogen receptor-β (Erβ(Esr2)) knockout mice. Surprisingly, apoptosis was reduced and cell proliferation was increased in sections from tumors of the WT E2mice compared with the WT control mice. These findings are probably due, in part, to a reduction in ERβ expression in colonic epithelial cells as the cells progressed from a non-malignant to a cancerous state as enhanced apoptosis was observed in normal colonocytes expressing higher levels of ERβ. Furthermore, epithelial cells within the tumors had dramatically increased ERα mRNA and protein expression compared with the non-diseased mice. We conclude that while E2treatment resulted in an overall suppression of colonic adenocarcinoma formation, reduced ERβ expression accompanied by enhanced ERα expression caused an altered colonocyte response to E2treatment compared with the earlier stages of colon cancer development. These data are the first examples of decreased ERβ expression concurrent with increased ERα expression as a disease develops and highlight the importance of understanding the timing of E2exposure with regard to the prevention of inflammation-associated colon cancer.

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Genetic and demographic effects of single wild-type immigrants on a mutant population of Tribolium castaneum

Canadian Journal of Genetics and Cytology ◽

10.1139/g86-139 ◽

1986 ◽

Vol 28 (6) ◽

pp. 1003-1008 ◽

Cited By ~ 1

Author(s):

Michael A. Delgado ◽

DuWayne C. Englert

Keyword(s):

Tribolium Castaneum ◽

Wild Type ◽

Gene Frequencies ◽

Treatment Groups ◽

Female Immigrant ◽

Rate Of Increase ◽

Wild Type Male ◽

Wild Type Female ◽

In The Wild ◽

Type Gene

The effects of single wild-type immigrants on populations of Tribolium castaneum initially homozygous for the antennapedia (ap) allele were examined in reference to gene frequencies and age structures. One population received a wild-type male, another received a wild-type female, and the control population received no wild-type immigrant. The rate of increase in the wild-type gene frequency was significantly higher in the female immigrant population. Rapid increase in heterozygosity for this population resulted in a higher average number of adults than for the other two treatment groups. No significant differences in the numbers of larvae and pupae were observed. Results indicated increased larval survivability to be the major factor in establishment of the wild-type gene and the sex of the immigrant in the rate of increase.Key words: Tribolium, population, selection, immigration, antennapedia.

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A model of chronic diabetic polyneuropathy: benefits from intranasal insulin are modified by sex and RAGE deletion

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00444.2016 ◽

2017 ◽

Vol 312 (5) ◽

pp. E407-E419 ◽

Cited By ~ 8

Author(s):

Cristiane L. de la Hoz ◽

Chu Cheng ◽

Paul Fernyhough ◽

Douglas W. Zochodne

Keyword(s):

Thermal Sensitivity ◽

Diabetic Polyneuropathy ◽

Preliminary Evidence ◽

Male Mice ◽

Intranasal Insulin ◽

Wild Type ◽

Advanced Glycosylation End Products ◽

Wild Type Female ◽

Grip Power ◽

Advanced Glycosylation

Human diabetic polyneuropathy (DPN) is a progressive complication of chronic diabetes mellitus. Preliminary evidence has suggested that intranasal insulin, in doses insufficient to alter hyperglycemia, suppresses the development of DPN. In this work we confirm this finding, but demonstrate that its impact is modified by sex and deletion of RAGE, the receptor for advanced glycosylation end products. We serially evaluated experimental DPN in male and female wild-type mice and male RAGE null (RN) mice, each with nondiabetic controls, during 16 wk of diabetes, the final 8 wk including groups given intranasal insulin. Age-matched nondiabetic female mice had higher motor and sensory conduction velocities than their male counterparts and had lesser conduction slowing from chronic diabetes. Intranasal insulin improved slowing in both sexes. In male RN mice, there was less conduction slowing with chronic diabetes, and intranasal insulin provided limited benefits. Rotarod testing and hindpaw grip power offered less consistent impacts. Mechanical sensitivity and thermal sensitivity were respectively but disparately changed and improved with insulin in wild-type female and male mice but not RN male mice. These studies confirm that intranasal insulin improves indexes of experimental DPN but indicates that females with DPN may differ in their underlying phenotype. RN mice had partial but incomplete protection from underlying DPN and lesser impacts from insulin. We also identify an important role for sex in the development of DPN and report evidence that insulin and AGE-RAGE pathways in its pathogenesis may overlap.

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NKG2D function protects the host from tumor initiation

Journal of Experimental Medicine ◽

10.1084/jem.20050994 ◽

2005 ◽

Vol 202 (5) ◽

pp. 583-588 ◽

Cited By ~ 227

Author(s):

Mark J. Smyth ◽

Jeremy Swann ◽

Erika Cretney ◽

Nadeen Zerafa ◽

Wayne M. Yokoyama ◽

...

Keyword(s):

De Novo ◽

Tumor Formation ◽

Wild Type ◽

Experimental Tumor ◽

Host Protection ◽

Ligand Expression ◽

Ifn Γ ◽

Deficient Mice ◽

Nkg2d Receptor ◽

Necrosis Factor

The activation NKG2D receptor has been shown to play an important role in the control of experimental tumor growth and metastases expressing ligands for NKG2D; however, a function for this recognition pathway in host protection from de novo tumorigenesis has never been demonstrated. We show that neutralization of NKG2D enhances the sensitivity of wild-type (WT) C57BL/6 and BALB/c mice to methylcholanthrene (MCA)-induced fibrosarcoma. The importance of the NKG2D pathway was additionally illustrated in mice deficient for either IFN-γ or tumor necrosis factor–related apoptosis-inducing ligand, whereas mice depleted of natural killer cells, T cells, or deficient for perforin did not display any detectable NKG2D phenotype. Furthermore, IL-12 therapy preventing MCA-induced sarcoma formation was also largely dependent on the NKG2D pathway. Although NKG2D ligand expression was variable or absent on sarcomas emerging in WT mice, sarcomas derived from perforin-deficient mice were Rae-1+ and immunogenic when transferred into WT syngeneic mice. These findings suggest an important early role for the NKG2D in controlling and shaping tumor formation.

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