The Inhibitory Activity of the AU-Rich RNA Element in the Human Papillomavirus Type 1 Late 3′ Untranslated Region Correlates with Its Affinity for the elav-Like HuR Protein

Sokolowski, Marcus; Furneaux, Henry; Schwartz, Stefan

doi:10.1128/jvi.73.2.1080-1091.1999

Cited by 55 publications

(23 citation statements)

References 53 publications

(106 reference statements)

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“…HuR and U2AF 65 both bind to the late UTR of HPV-31 [Cumming et al, 2002], HuR also binds to the AU-rich instability element in HPV-1 [Sokolowski et al, 1997[Sokolowski et al, , 1999 and U2AF 65 to a negative regulatory element in HPV-16 [Koffa et al, 2000]. The expression profile for these proteins would support a role in inhibiting late gene expression.…”

Section: Discussionmentioning

confidence: 98%

“…It has been demonstrated that a number of cellular RNA-binding proteins interact with regulatory RNA elements on HPV mRNAs, the late mRNAs in particular. It has been shown for example, that hnRNP C1/C2 and HuR interact with an AU-rich RNA instability element in the late 3 0 UTR of HPV-1 [Sokolowski et al, 1997[Sokolowski et al, , 1999Sokolowski and Schwartz, 2001], CstF64, U2AF 65 and HuR along with ASF/SF2 bind to a negative element within the HPV-16 late UTR RNA [Dietrich-Goetz et al, 1997;Koffa et al, 2000;McPhillips et al, 2004], and that the late UTR of HPV-31 interacts with CstF64, HuR and U2AF 65 [Cumming et al, 2002]. In addition hnRNP A1 was shown to bind to multiple splicing silencers in the HPV-16 L1 coding region thereby inhibiting splicing of the late mRNAs [Zhao et al, 2004], hnRNP K and poly(rC) binding proteins interact with inhibitory elements within HPV-16 L2 reducing the expression of the late genes [Collier et al, 1998], and hnRNP H binds to motifs within HPV-16 L2 promoting the use of the early polyadenylation signal .…”

Section: Introductionmentioning

confidence: 99%

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Increased expression of cellular RNA‐binding proteins in HPV‐induced neoplasia and cervical cancer

Fay¹,

Kelehan

Lambkin³

et al. 2009

Journal of Medical Virology

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The expression profile of a panel of RNA-binding proteins (heterogeneous ribonucleoprotein (hnRNP) A1, hnRNP C1/C2, hnRNP H, hnRNP I, ASF/SF2, SR proteins, HuR and U2AF(65)) and markers of differentiation, proliferation and neoplasia (cytokeratin (CK) 13, CK-14, proliferating cell nuclear antigen (PCNA), Syndecan-1 and p16INK4a) were analyzed in 50 formalin fixed paraffin embedded cervical tissues using immunohistochemistry. The samples included histologically normal cervical epithelium, human papillomavirus (HPV) induced low-grade and high-grade pre-malignant lesions and cervical cancers. All samples were tested for HPV DNA using nested PCR. Forty-nine of the 50 tissue samples tested positive for HPV, 27 tissue samples (54%) were HPV-16 positive and 4 samples (8%) were HPV-18 positive. The immunohistochemistry results detected different expression levels of the various proteins in basal epithelial cells in histologically normal epithelium followed by an increase in expression in the intermediate layers, whereas the superficial layers remained negative for all tested RNA-binding proteins. Expression of all RNA-binding proteins increased in neoplastic lesions and highest expression was detected in cervical cancers. p16INK4a had a stronger association with high-grade lesions when compared with the RNA-binding proteins. The expression profile of the RNA-binding proteins is similar to PCNA expression in histologically normal epithelium as well as in lesions (low-grade and high-grade) and cervical cancers. As PCNA expression has been suggested to mimic HPV E6/E7 expression in cervical epithelium, the results suggest the RNA-binding protein analyzed here regulate HPV early gene expression directly and late gene expression indirectly.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Increased expression of cellular RNA‐binding proteins in HPV‐induced neoplasia and cervical cancer

Fay¹,

Kelehan

Lambkin³

et al. 2009

Journal of Medical Virology

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“…HeLa cell nuclear extracts were prepared according to the method of Dignam et al (1983). GST-hnRNP A1 was prepared as described previously (Sokolowski et al, 1999). Twenty micrograms of nuclear extract or fifty nanograms of recombinant hnRNP A1 was used for each UV cross-linking.…”

Section: Uv Cross-linking and Preparation Of Cellular Extracts And Rementioning

confidence: 99%

Identification of a 17-nucleotide splicing enhancer in HPV-16 L1 that counteracts the effect of multiple hnRNP A1-binding splicing silencers

Zhao

Fay²,

Lambkin³

et al. 2007

Virology

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Human papillomavirus type 16 (HPV-16) infections can in rare cases persist and cause lesions that may progress to cervical cancer. Cells in the lesions are not permissive for virus production, nor are cervical cancer cells. The intracellular environment is such that it prevents production of the highly immunogenic, viral structural proteins L1 and L2. One may speculate that inhibition of L1 and L2 expression is a prerequisite for persistence and cancer progression. We have therefore investigated how expression of HPV-16 L1 is regulated. We found that the only splice site in the HPV-16 late region, which is used to produce L1 mRNAs, is under control of a splicing enhancer located in the 17 nucleotides immediately downstream of the splice site. However, the function of this enhancer in cervical cancer cells is largely overshadowed by multiple splicing silencers in the late region which bind to hnRNP A1. High levels of hnRNP A1 therefore inhibit HPV-16 L1 expression. Immunohistological analysis of cervical epithelia revealed that hnRNP A1 is expressed primarily in the lower layers of the epithelium. hnRNP A1 is undetectable in terminally differentiated cells that can express HPV-16 late genes, which supports the conclusion that high levels of hnRNP A1 inhibit HPV-16 L1 expression.

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“…Mutant mice lacking TTP develop cachexia, arthritis and autoimmunity as a consequence of overexpressed TNF‐α mRNA and protein (Taylor et al ., 1996). In addition to TTP, Hel‐N1 (Levine et al ., 1993), HuR (Myer et al ., 1997; Fan and Steitz, 1998; Peng et al ., 1998; Sokolowski et al ., 1999), AUF1 [heterogeneous nuclear ribonucleoprotein (hnRNP) D] (Zhang et al ., 1993) and TIAR (Gueydan et al ., 1999) are ARE‐binding proteins that have been proposed to regulate the expression of TNF‐α (Sakai et al ., 1999). Hel‐N1 (Levine et al ., 1993; Gao et al ., 1994; Ford et al ., 1999) and HuR (Myer et al ., 1997; Fan and Steitz, 1998; Peng et al ., 1998; Sokolowski et al ., 1999) stabilize ARE‐containing transcripts, whereas AUF1 destabilizes these transcripts (Loflin et al ., 1999).…”

Section: Introductionmentioning

confidence: 99%

TIA-1 is a translational silencer that selectively regulates the expression of TNF-α

Piecyk

Wax

Beck³

et al. 2000

The EMBO Journal

474

568

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contributed equally to this work TIA-1 and TIAR are related proteins that bind to an AU-rich element (ARE) in the 3¢ untranslated region of tumor necrosis factor alpha (TNF-a) transcripts. To determine the functional signi®cance of this interaction, we used homologous recombination to produce mutant mice lacking TIA-1. Although lipopolysaccharide (LPS)-stimulated macrophages derived from wild-type and TIA-1 ±/± mice express similar amounts of TNF-a transcripts, macrophages lacking TIA-1 produce signi®cantly more TNF-a protein than wild-type controls. The half-life of TNF-a transcripts is similar in wild-type and TIA-1 ±/± macrophages, indicating that TIA-1 does not regulate transcript stability. Rather, the absence of TIA-1 signi®cantly increases the proportion of TNF-a transcripts that associate with polysomes, suggesting that TIA-1 normally functions as a translational silencer. TIA-1 does not appear to regulate the production of interleukin 1b, granulocyte±macrophage colony-stimulating factor or interferon g, indicating that its effects are, at least partially, transcript speci®c. Mice lacking TIA-1 are hypersensitive to the toxic effects of LPS, indicating that this translational control pathway may regulate the organismal response to microbial stress.

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The Inhibitory Activity of the AU-Rich RNA Element in the Human Papillomavirus Type 1 Late 3′ Untranslated Region Correlates with Its Affinity for the elav-Like HuR Protein

Cited by 55 publications

References 53 publications

Increased expression of cellular RNA‐binding proteins in HPV‐induced neoplasia and cervical cancer

Increased expression of cellular RNA‐binding proteins in HPV‐induced neoplasia and cervical cancer

Identification of a 17-nucleotide splicing enhancer in HPV-16 L1 that counteracts the effect of multiple hnRNP A1-binding splicing silencers

TIA-1 is a translational silencer that selectively regulates the expression of TNF-α

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