Targeted degradation of the retinoblastoma protein by human papillomavirus E7-E6 fusion proteins.

Scheffner, Martin; Münger, Karl; Huibregtse, Jon M.; Howley, Peter

doi:10.1002/j.1460-2075.1992.tb05307.x

Cited by 120 publications

(79 citation statements)

References 51 publications

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“…The E7 oncoproteins of high risk HPVs in cervical cancer cells inhibit the function of Rb and cause its degradation (42)(43)(44). Here, nucleolin localization in six HPV16-positive carcinomas and high grade intraepithelial lesions and four different normal (HPV-free) tissues of human cervix was analyzed by immunohistochemistry.…”

Section: Resultsmentioning

confidence: 99%

Cell Cycle-controlled Interaction of Nucleolin with the Retinoblastoma Protein and Cancerous Cell Transformation

Grinstein

Shan

Karawajew

et al. 2006

Journal of Biological Chemistry

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Retinoblastoma protein (Rb) is a multifunctional tumor suppressor, frequently inactivated in certain types of human cancer. Nucleolin is an abundant multifunctional phosphoprotein of proliferating and cancerous cells, recently identified as cell cycle-regulated transcription activator, controlling expression of human papillomavirus type 18 (HPV18) oncogenes in cervical cancer. Here we find that nucleolin is associated with Rb in intact cells in the G 1 phase of the cell cycle, and the complex formation is mediated by the growth-inhibitory domain of Rb. Association with Rb inhibits the DNA binding function of nucleolin and in consequence the interaction of nucleolin with the HPV18 enhancer, resulting in Rb-mediated repression of the HPV18 oncogenes. The intracellular distribution of nucleolin in epithelial cells is Rb-dependent, and an altered nucleolin localization in human cancerous tissues results from a loss of Rb. Our findings suggest that deregulated nucleolin activity due to a loss of Rb contributes to tumor development in malignant diseases, thus providing further insights into the molecular network for the Rb-mediated tumor suppression.Nucleolin is an abundant multifunctional phosphoprotein of proliferating and cancerous cells (1, 2) (reviewed in Ref.3). High levels of nucleolin expression are related to poor clinical prognosis for certain cancer types (2, 4). A role of nucleolin in activation and repression of gene transcription as well as in regulation of RNA metabolism has been reported (5-7). Nucleolin is a subunit of the transcription factor LR1, which activates expression of the c-myc gene and the EBNA-1 (Epstein-Barr virus nuclear antigen 1) gene in B-cell lymphomas (7-9). Nucleolin is also directly involved in post-transcriptional inhibition of the p53 gene expression (10). As activator of transcription of HPV18 2 oncogenes in cervical cancer cells, nucleolin has oncogenic potential (11). Nucleolin controls the chromatin structure of the HPV18 enhancer in vivo and is directly linked to HPV18-induced cervical cancer formation (11). Nucleolin is a substrate of cyclin-dependent kinases (CDKs), CDK1, CDK4, and CDK2 (12, 13), and its DNA binding activity is most prominent in the S phase of the cell cycle (11). Here we report a functional interaction of nucleolin with Rb, related to cell transformation.Rb is a prototypical tumor suppressor, frequently inactivated in certain types of human cancer, and it controls cell proliferation, differentiation, and survival (14). Therefore, it is important to work out molecular mechanisms of Rb-mediated tumor suppression to understand the cancer disease process (14, 15). Rb functions to constrain cell proliferation by providing a cell cycle checkpoint between the G 1 and S phases (16,17). Phosphorylation of Rb by cyclin-dependent kinases is initiated in mid-G 1 phase, and Rb phosphorylation is associated with G 1 /S transition and S phase progression (18,19). Hypophosphorylated Rb restrains cell proliferation, in part by targeting E2F transcription factors (20 -23)...

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Section: Resultsmentioning

confidence: 99%

Cell Cycle-controlled Interaction of Nucleolin with the Retinoblastoma Protein and Cancerous Cell Transformation

Grinstein

Shan

Karawajew

et al. 2006

Journal of Biological Chemistry

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“…Similarly, BPV-1 E6 (BE6), while binding E6-AP, fails to either complex with p53 or degrade other associated proteins in an in vitro degradation assay, implying that BE6 association with E6-AP may have functions other than the targeting of p53 (Chen et al, 1995;Sche ner et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Association of Bovine Papillomavirus Type 1 E6 oncoprotein with the focal adhesion protein paxillin through a conserved protein interaction motif

1998

Oncogene

120

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We have found that the E6 oncoprotein of Bovine Papillomavirus Type 1 (BE6) as well as the E6 protein of the cancer associated HPV-16 (16E6) interact with the focal adhesion protein paxillin. Mutational analysis of paxillin revealed that BE6 binds paxillin through small protein interaction motifs called LD motifs that have been previously identi®ed as important in regulating association of paxillin with vinculin and focal adhesion kinase (FAK), and that BE6 can interact with at least two separate binding sites on paxillin. The LD motifs of paxillin that bind BE6 share homology with the E6 binding site of E6-AP, a ubiquitin ligase that together with 16E6 targets the degradation of the p53 tumor suppressor. Paxillin binding to BE6 excludes simultaneous binding to E6-AP. Mutational analysis of BE6 can distinguish the interaction of BE6 with E6-AP compared to paxillin and revealed that the interaction of BE6 with paxillin may be necessary for the induction of anchorage independent growth of cells by BE6.

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“…[18][19][20] HR-HPV oncoproteins also initiate p53 and pRb degradation. 19,21,22 These HPV actions influence expression of other tumor suppressor proteins such as p16 INK4a within pRb pathway. 23 Therefore, these cellular proteins, i.e., pRb, p53 and p16 INK4a are considered surrogate markers for HPV involvement.…”

mentioning

confidence: 99%

Biological activity of probable/possible high‐risk human papillomavirus types in cervical cancer

Halec

Schmitt

Dondog

et al. 2012

Intl Journal of Cancer

111

155

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Judging the carcinogenicity of human papillomavirus (HPV) types rarely found in cervical cancer (CxCa) is hindered by lack of studies of their biological activity in cancer tissues. To asses transcriptional activity of HPV types, we have developed ultrashort amplimer, splice-site specific, E6*I mRNA RT-PCR assays for 12 high-risk (HR)-HPV (IARC Group 1) and eight probable/ possible high-risk (pHR)-HPV types (IARC Group 2A/B carcinogens). Previously unreported E6*I splice sites of the six pHR-HPV types 26, 53, 67, 70, 73 and 82 were identified by cloning and sequencing. We analyzed 97 formalin-fixed paraffin-embedded (FFPE) Mongolian CxCa biopsies for presence of HPV DNA by two sensitive genotyping assays, for E6*I transcripts of all HR-/ pHR-HPV types identified and for expression of HPV surrogate markers p16 INK4a , pRb and p53. E6*I of at least one HR-/pHR-HPV was expressed in 94 (98%) of cancer tissues including seven with pHR-HPV types 26, 66, 70 or 82 as single transcribed types. Fifty-eight of E6*I mRNA transcribing cases were analyzable by immunohistochemistry and displayed p16 INK4a overexpression in 57 (98%), pRb downregulation in 56 (97%) and p53 downregulation in 36 (62%) tissues. The newly developed E6*I mRNA RT-PCR assays appeared to be highly sensitive method to analyze HPV transcription in FFPE materials. Our finding of viral oncogene transcription of pHR-HPV types 26, 66, 70 and 82 in cervical tumors, in the absence of any other transcriptionally active HR-type and with p16 INK4a overexpression and pRb downregulation, may support a reassessment of the carcinogenicity classification of these pHR-HPV types.Human papillomaviruses (HPV) with currently more than 150 types defined are a complex group differing in tropism and carcinogenic potential. Detection of HPV DNA in 99.7% of cervical cancer (CxCa) cases has established HPV as an etiological factor for CxCa development. 1,2 Epidemiological studies have demonstrated that 20 mucosal HPV types from five phylogenetically related species of the genus alpha (a5, a6, a7, a9 and a11-termed as ''high-risk clade'') are consistently found as single HPV infections in CxCa worldwide. [3][4][5][6] Based on their frequency in CxCa and available biological data, 12 of these types, i.e., types 16,18,31,33,35,39, 45, 51, 52, 56, 58 and 59 have been defined as carcinogens (IARC Group 1A)-hereafter referred to as high-risk (HR)-HPV. For eight other types, in the high-risk clade, i.e., types 26, 53, 66, 67, 68, 70, 73 and 82, the combination of their low frequency, lack of data on their active transcription and their transforming potential in model systems, has led them to be classified as only probable/possible carcinogens (IARC Groups 2A and 2B)-hereafter referred to as possible highrisk (pHR)-HPV types. 7 In the era of HPV-based cervical cancer precursor screening and of type-specific HPV vaccination, understanding the oncogenic properties of individual

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Targeted degradation of the retinoblastoma protein by human papillomavirus E7-E6 fusion proteins.

Cited by 120 publications

References 51 publications

Cell Cycle-controlled Interaction of Nucleolin with the Retinoblastoma Protein and Cancerous Cell Transformation

Cell Cycle-controlled Interaction of Nucleolin with the Retinoblastoma Protein and Cancerous Cell Transformation

Association of Bovine Papillomavirus Type 1 E6 oncoprotein with the focal adhesion protein paxillin through a conserved protein interaction motif

Biological activity of probable/possible high‐risk human papillomavirus types in cervical cancer

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