Genomic organization of the human ubiquitin-conjugating enzyme gene, UBE2L6 on chromosome 11q12

Ardley, Helen C.; Rose, Stephen A.; Tan, Nancy G.S.; Leek, J.P.; Markham, Alexander F.; Robinson, Philip A.

doi:10.1159/000015593

Cited by 6 publications

(6 citation statements)

References 11 publications

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“…Coordinated induction of the novel ubiquitin family ISGs, ISG15, USP18, and UBE1L or UBE-2L6, may be important for control of cell growth suppression and apoptosis. (23,37,(60)(61)(62) UBE-1L was identified as an activating enzyme for ISG15. (63) ISG15 is conjugated to intracellular proteins via an isopeptide bond similar to ubiquitin, (60)(61)(62) may influence IFN signaling, and is also secreted.…”

Section: Discussionmentioning

confidence: 99%

“…(23,(60)(61)(62) The UBE-2L6 gene, homologous to yeast gene UBC9 that is critical in progression from G 2 to M, encodes UbcH8, a ubiquitin-conjugating enzyme that belongs a multigene family with functional redundancy. (37) USP18, an ISG15-specific 17 protease, (23) is crucial for cellu- lar balance of ISG15-conjugated proteins. USP18 2/2 mice have massive accumulation of ISG15 conjugates and cellular necrosis.…”

Section: Discussionmentioning

confidence: 99%

“…4B). Quantitative PCR was used to assess comparative magnitude and kinetics of augmentation by IFN-a2 and IFN-b for genes SP100, a promyelocytic leukemia (PML)-associated gene, (32) TNFstimulated gene 6, (33,34) augmented in prostate carcinoma (AIPC) gene, (35) a cyclin-E and Myc-associated protein, (36) ubiquitin E 2 -like protein (UBEL-2), (37) and a ubiquitin-specific protease (23,38) (Fig. 5).…”

Section: Confirmation By Northern Blot and Rt-pcr Of Kinetics Of Indumentioning

confidence: 99%

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Novel Growth and Death Related Interferon-Stimulated Genes (ISGs) in Melanoma: Greater Potency of IFN-βCompared with IFN-α2

Leaman

Chawla‐Sarkar

Jacobs

et al. 2003

Journal of Interferon & Cytokine Research

113

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Interferon (IFN)-dependent cellular effects are mediated by transcriptional induction of responsive genes, collectively referred to as IFN-stimulated genes (ISGs). Which ISGs regulate the potent antiviral, antiproliferative, apoptosis-inducing, antiangiogenic, and immunologic effects of IFNs remains largely undetermined. To identify genes that might be useful for predicting or targeting apoptosis induction in response to IFNs, WM9 melanoma cells were assessed. WM9 cells had equivalent antiviral activity in response to IFN-beta and IFN-alpha2 but underwent apoptosis only in response to IFN-beta. RNA samples from WM9 cells and WM35 cells, a second melanoma cell line, treated with IFN-alpha2 or IFN-beta were assessed on oligonucleotide arrays. For 95% of genes assessed, IFN-beta was more potent than IFN-alpha2 in inducing ISG expression. Using a 22,000-gene oligonucleotide array, the largest yet reported for assessing ISG induction, approximately 910 genes were identified as induced by IFN-beta at 500 U/ml, and 260 ISGs were identified as significantly induced by IFN-beta at both 50 and 500 U/ml. Of these 260, 209 were defined as new ISGs based on the array analysis. Confirmation by Northern blot or semiquantitative or quantitative PCR was undertaken for 28, and all were confirmed. Nearly half of the 260 genes were functionally categorized as encoding growth-regulatory proteins. Of the 104 with described growth-regulatory function, 71 were induced more than three times by 500 U/ml and twice by 50 U/ml IFN-beta, and 48 of these were new ISGs. Included in this latter category were tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), XIAP-associated factor 1 (XAF1), galectin 9, a cyclin E binding protein, amphiphysin 1, MyD88, and several ubiquitin pathway genes. The diversity of stimulated genes suggests the full therapeutic potential of IFN regulation of gene expression has yet to be realized.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Confirmation By Northern Blot and Rt-pcr Of Kinetics Of Indumentioning

confidence: 99%

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Novel Growth and Death Related Interferon-Stimulated Genes (ISGs) in Melanoma: Greater Potency of IFN-βCompared with IFN-α2

Leaman

Chawla‐Sarkar

Jacobs

et al. 2003

Journal of Interferon & Cytokine Research

113

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“…FISH of SJSA‐1 metaphase spreads was undertaken as previously described [25]. Chromosome 12 paints (Vysis, Downers Grove, IL) were used to identify the distribution of all chromosome 12 sequences.…”

Section: Methodsmentioning

confidence: 99%

Phenotypic changes associated with DYNACTIN‐2 (DCTN2) over expression characterise SJSA‐1 osteosarcoma cells

Bransfield¹,

Askham²,

Leek³

et al. 2005

Molecular Carcinogenesis

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DYNACTIN-2 (DCTN2) localises to chromosome 12q13-q15, a region prone to stable amplification in several cancers. Transient DCTN2 overexpression has a significant impact on cellular phenotype primarily due to disruption of the DYNEIN-dynactin motor. Changes reported include alterations of microtubule-directed movement of molecular (e.g. TP53) and organelle (e.g. Golgi) cargoes towards the nucleus, centrosome biology, cellular movement and mitosis with a potential predisposition to mitotic block and polyploidy. These changes would be expected to be of relevance to carcinogenesis. To investigate this, we report the first study of DCTN2 genomic amplification and sustained DCTN2 overexpression in cancer cells. QFMPCR was employed to characterise the extent of chromosome 12q13-q15 amplicons in SJSA-1, SJRH30, U373MG and CCF-STTG1 cancer cells. DCTN2 amplification was present in SJSA-1, U373MG and SJRH30 cells, yet was incomplete at the 5'-end in SJRH30 cells. Only SJSA-1 cells were characterised by DCTN2 overexpression on Western blot analyses. Microscopy studies distinguished SJSA-1 cells by greater DCTN2 immunofluorescence and diminished centrosome and 58K protein Golgi-marker focus compared to SJRH30 cells. Indirect evidence derived from the published work of others indicated that TP53 transport into the nucleus was unimpaired. Furthermore, we observed that SJSA-1 cells were easy to propagate. In conclusion, persistent DCTN2 overexpression can be tolerated in SJSA-1 cancer cells despite phenotypic abnormalities predicted from transient overexpression studies. This preliminary study does not support a major role for DCTN2 overexpression in carcinogenesis, although further studies would be necessary to confirm this.

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“…Two of the proteins that are significantly down-regulated are the ubiquitin cross-reacting protein (UCRP, also known as interferon stimulated gene 15, ISG15) and UBE2L6 (UbcH8). UCRP and UBE2L6 (UbcH8) belong to the regulatory network that modulates the function and targeted degradation of specific proteins in a cell [6][7][8][9][10]. One significant possible consequence of the downregulation of such a protein could be enhancement of the growth factor receptors [11,12] and hence the acceleration of the growth rate of the affected cells.…”

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confidence: 99%

Down-regulation of UCRP and UBE2L6 in BRCA2 knocked-down human breast cells

Tripathi

Chaudhuri

2005

Biochemical and Biophysical Research Communications

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To understand the effects of the transient ablation of BRCA2 gene expression in dividing human breast cells we transiently knocked down BRCA2 mRNA in HMEC and other cells. Microarray analysis of mRNAs revealed the down-regulation of the mRNAs of ubiquitin cross-reacting protein (UCRP) and the E2 enzyme that help conjugating UCRP to its target proteins, namely UBE2L6 (UbcH8), in BRCA2 ablated cells. UCRP is an interferon regulated protein, involved in cell growth and cell cycle events by participating in the degradation/modulation of cell cycle regulatory proteins. Quantitative-PCR and Northern analysis confirmed down-regulation of UCRP and UBE2L6 with BRCA2 knock down, respectively. Since UCRP and UCRPylation have critical roles in the innate immunity against viral infection and during pregnancy, our observation may indicate new roles of the BRCA2 protein. KeywordsBRCA2; UCRP; ISG15; UBE2L6; UbcH8; siRNA; shRNA; H1 RNA promoter; Antisense phosphorothioate; Microarray BRCA2 is a tumor suppressor protein with diverse functions [1,2]. BRCA2 deficiency has been attributed as the cause for many cases of breast, ovarian, and pancreatic carcinoma [1,2]. BRCA2 deficiency may be caused by the molecular defects in the BRCA2 genes or due to sporadic reasons. BRCA2 gene is not expressed in non-dividing cells and the rate of expression of this protein is increased with the rate of cell proliferation [3][4][5]. This growth dependent turn-on/turn-off mechanism of this gene is not well understood. Any number of environmental cues may influence the turn-on event and may initiate a molecular domino effect leading to DNA damage and oncogenesis. While undue expression of BRCA2 protein in non-dividing cells may initiate apoptosis, failure of the cell to produce appropriate amount of BRCA2 corresponding to the growth rate of the cell may also be detrimental. Since majority of the breast cancer cases are sporadic [1][2][3][4][5], some of such cancers may have initiated due to the transient absence of BRCA2 during the proliferative stages of the breast cells.The molecular consequences of transient BRCA2 deficiency in the breast cells are not known. We report here our preliminary observations on the effect of transient ablation of BRCA2 gene expression on human mammary epithelial cells (HMEC) and BT549 human breast carcinoma cells. Microarray analysis of the mRNAs isolated from these BRCA2 knocked down cells showed a limited number of genes that are down-regulated as an Materials and methods Knockdown of BRCA2 gene expressionWe took three parallel approaches for the transient knock down of BRCA2 gene expression.In one, we used anti-BRCA2 antisense gapmer oligonucleotides (sense control: 5′-ATGCCTATTGGATCCAA-3′; antisense: 5′-TTGGATCCAATAGGCAT-3′). In the gapmer (custom synthesized from Tri-link Biotechnology, CA) the terminal five nucleotides have 2-methoxy ribose and the middle 7 nucleotides are phosphorothioate. These oligos were used previously [13,14] to knock down BRCA2 in human cells. In the second approach, we used BRCA2...

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Genomic organization of the human ubiquitin-conjugating enzyme gene, UBE2L6 on chromosome 11q12

Cited by 6 publications

References 11 publications

Novel Growth and Death Related Interferon-Stimulated Genes (ISGs) in Melanoma: Greater Potency of IFN-βCompared with IFN-α2

Novel Growth and Death Related Interferon-Stimulated Genes (ISGs) in Melanoma: Greater Potency of IFN-βCompared with IFN-α2

Phenotypic changes associated with DYNACTIN‐2 (DCTN2) over expression characterise SJSA‐1 osteosarcoma cells

Down-regulation of UCRP and UBE2L6 in BRCA2 knocked-down human breast cells

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