Huntingtin interacting protein 1 as a histopathologic adjunct in the diagnosis of Merkel cell carcinoma

Marghalani, Siham; Feller, John Kyle; Mahalingam, Meera; Mirzabeigi, Marjan

doi:10.1111/ijd.12454

Cited by 7 publications

(9 citation statements)

References 16 publications

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“…In addition to the conditional nature of this allele that allows for expression of HIP1 in specific tissues at specific times, there were other potential advantages of this targeting strategy. First, since HIP1 is expressed at high levels in many cancers (24,25,29,30), humanization of a mouse allele could be of future use for preclinical in vivo HIP1-targeted drug testing. Second, this type of humanization addresses the question of whether the many introns of the large, 250-kb Hip1 locus are required for regulation of the Hip1 gene.…”

Section: Resultsmentioning

confidence: 99%

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Deficiency of the Endocytic Protein Hip1 Leads to Decreased Gdpd3 Expression, Low Phosphocholine, and Kypholordosis

Wijayatunge

Holmstrom

Foley

et al. 2018

Molecular and Cellular Biology

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Deficiency of huntingtin-interacting protein 1 (Hip1) results in degenerative phenotypes. Here we generated a deficiency allele where a floxed transcriptional stop cassette and a human cDNA were knocked into intron 1 of the mouse locus.-mediated germ line excision of the stop cassette resulted in expression of HIP1 and rescue of the knockout phenotype.-mediated excision led to HIP1 expression in spleen, kidney and liver, and also rescued the phenotype. In contrast, -mediated, brain-specific HIP1 expression did not rescue the phenotype. Metabolomics and microarrays of several knockout tissues identified low phosphocholine (PC) levels and low glycerophosphodiester phosphodiesterase domain containing 3 (Gdpd3) gene expression. Since Gdpd3 has lysophospholipase D activity that results in the formation of choline, a precursor of PC, downregulation could lead to the low PC levels. To test whether contributes to the deficiency phenotype, we generated knockout mice. Double knockout of and worsened the Hip1 phenotype. This suggests that Gdpd3 compensates for Hip1 loss. More-detailed knowledge of how deficiency leads to low PC will improve our understanding of HIP1 in choline metabolism in normal and disease states.

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Section: Resultsmentioning

confidence: 99%

“…Gdpd3 knockout mice show no changes in PC. Gdpd3 has lysophosphatidylcholine (LPC)-specific phospholipase D (lysoPLD) activity that can generate lysophospha-tidic acid (LPA) and choline (30,34). In the first step in the biosynthesis of phosphatidylcholine, choline is phosphorylated to generate phosphocholine (PC).…”

Section: Resultsmentioning

confidence: 99%

Deficiency of the Endocytic Protein Hip1 Leads to Decreased Gdpd3 Expression, Low Phosphocholine, and Kypholordosis

Wijayatunge

Holmstrom

Foley

et al. 2018

Molecular and Cellular Biology

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show abstract

“…In addition to the conditional nature of this allele that allows for expression of HIP1 in specific tissues at specific times, there were other potential advantages of this targeting strategy. First, since HIP1 is expressed at high levels in many cancers ( 24, 25, 35, 36 ), humanization of a mouse allele could be of future use for preclinical in vivo HIP1 targeted drug testing. Second, this type of humanization addresses the question of whether the many introns of the large 250 Kb Hip1 locus are required for regulation of the Hip1 gene.…”

Section: Resultsmentioning

confidence: 99%

“…The role of HIP1 in leukemia (15) and lung cancer ( 20-22 ) as an oncogenic fusion partner and the necessity of Hip1 for mouse homeostasis are well established ( 11, 12 ). Additionally, HIP1 itself is upregulated in many cancers ( 24, 25, 35, 36 ) and prognostic in prostate cancer (25). However, mechanisms for how HIP1 overexpression contributes to transformation ( 24, 26 ) and how its deficiency in mice leads to degeneration are not known.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of the Endocytic ProteinHip1Leads to DecreasedGdpd3expression, Low Phosphocholine, and Kypholordosis

Wijayatunge

Holmstrom

Foley

et al. 2018

Preprint

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47Deficiency of huntingtin interacting protein 1 (Hip1) results in degenerative phenotypes. 48Here we generated a Hip1 deficiency allele where a floxed transcriptional stop-cassette 49 and a human HIP1 cDNA were knocked-in to intron 1 of mouse Hip1 locus. CMV-Cre-50 mediated germline excision of the stop-cassette resulted in expression of HIP1 and rescue 51 of the Hip1 knockout phenotype. Mx1-Cre-mediated excision led to HIP1 expression in 52 spleen, kidney and liver, and also rescued the phenotype. In contrast, GFAP-Cre-53 mediated HIP1 expression in brain did not rescue the phenotype. Metabolomics and 54 microarrays of several Hip1 knockout tissues identified low phosphocholine (PC) levels 55 and low Glycerophosphodiester Phosphodiesterase Domain Containing 3 (Gdpd3) 56 expression. Since Gdpd3 has lysophospholipase D activity that results in the formation of 57 choline, a precursor of PC, Gdpd3 downregulation could lead to the low PC levels. To 58 test if Gdpd3 contributes to the Hip1 deficiency phenotype, we generated Gdpd3 59 knockout mice. Double knockout of Gdpd3 and Hip1 worsened the Hip1 phenotype. This 60 suggests that Gdpd3 compensates for Hip1 loss. More detailed knowledge of how Hip1 61 deficiency leads to low PC will improve our understanding of HIP1 in choline 62 metabolism in normal and disease states. 63 64 65 amplified from pcDNA3-hHip1 plasmid. The IRES (~0.6 kb) and eGFP (~0.9 kb) 128 sequences were amplified from pIRES2-AcGFP1 and pEGFP-N1 plasmid, respectively. 129The final vector was obtained by standard molecular cloning. Aside from the 130 homology arms, the final vector also contains a Lox-Stop-Lox cassette (~1.5 kb), mHip1 131 partial intron1+ partial exon 2, hHip1 cDNA, IRES, EGFP + polyA, Frt sequences flanking 132 the Neo expression cassette (the neo cassette was used for positive selection of the 133 electroporated ES cells), and a DTA expression cassette (for negative selection of the ES 134

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“…Analysis by western blot showed more than 50 cancer cell lines had high levels of HIP1 protein7. Similarly, overexpression of HIP1 gene was also observed in multiple human cancers including prostate cancer8, breast cancer9, brain tumor10, Merkel cell carcinomas11 and lymphoma12. Furthermore, in vitro analysis of the effects of HIP1 overexpression on cells indicated that it can transform fibroblasts9.…”

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confidence: 99%

Prognostic significance of huntingtin interacting protein 1 expression on patients with acute myeloid leukemia

Wang

Guo

et al. 2017

Sci Rep

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Huntingtin interacting protein 1 (HIP1) is an endocytic protein which is overexpressed in a variety of human cancers and involved in cancer-causing translocation in leukemia. However, the prognostic impact of HIP1 expression on AML remains unclear. In this study, quantification of HIP1 transcript by real-time quantitative PCR in bone marrow blasts was performed in 270 AML patients. As a result, high HIP1 expression was seen more frequently in older patients, M4/M5 morphology and genes of NPM1 and DNMT3A mutations, and underrepresented in favorable karyotype subgroups and CEBPA double allele mutations in our AML patients. We also found high HIP1 expressers showed lower levels of hemoglobin. In addition, overexpression of HIP1 was associated with an inferior overall survival. The prognostic value of HIP1 expression was validated in patients from an independent TCGA cohort. Notably, up-regulation of miR-16, miR-15a, miR-28 and miR-660 were seen in high HIP1 expressers from the two independent cohorts. In vitro, interfereing of HIP1 expression by siRNA suppressed the proliferation of leukemic cells, and downregulation of these miRNAs were seen in THP-1 and Kasumi cell lines after silencing HIP1 expression. In conclusion, the HIP1 gene expression might serve as a reliable predictor for overall survival in AML patients.

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Huntingtin interacting protein 1 as a histopathologic adjunct in the diagnosis of Merkel cell carcinoma

Cited by 7 publications

References 16 publications

Deficiency of the Endocytic Protein Hip1 Leads to Decreased Gdpd3 Expression, Low Phosphocholine, and Kypholordosis

Deficiency of the Endocytic Protein Hip1 Leads to Decreased Gdpd3 Expression, Low Phosphocholine, and Kypholordosis

Deficiency of the Endocytic ProteinHip1Leads to DecreasedGdpd3expression, Low Phosphocholine, and Kypholordosis

Prognostic significance of huntingtin interacting protein 1 expression on patients with acute myeloid leukemia

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