The Role of Human Papillomavirus 16 E6 in Anchorage-Independent and Invasive Growth of Mouse Tonsil Epithelium

Hoover, A.; Spanos, William C.; Harris, George F.; Anderson, Mary E.; Klingelhutz, Aloysius J.; Lee, John H.

doi:10.1001/archotol.133.5.495

Cited by 74 publications

(112 citation statements)

References 33 publications

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“…The addition of Ras v12 to cells expressing E6/E7 allowed invasive tumorigenic growth. The results showed not only that the mice developed subcutaneous nodules but also that the cells comprising these nodules directly invaded surrounding muscle, bone, and nerve, resulting in paralysis (19). We also show that in MTECs, E6 alone is sufficient to induce this same invasive growth in combination with Ras v12 .…”

Section: E6 Induces Aig In Mtecs Via a Pdz-dependent Mechanismmentioning

confidence: 53%

“…Whole-cell lysates were harvested at 4°C with protein lysis buffer as previously described (19). Expression of human p53 was measured by immunoblotting using 25 g total cellular proteins with p53 antibody (OP-43; CalBiochem, San Diego, CA) at a 1:1,000 dilution and a standard Western blotting technique.…”

Section: Methodsmentioning

confidence: 99%

“…In vivo growth was assayed using previously described techniques (19). All experiments were performed in accordance with institutional and national guidelines and regulations, with the protocol reviewed and approved by the Animal Care Committee at the University of Iowa.…”

Section: Methodsmentioning

confidence: 99%

“…Normal HTECs and MTECs were isolated from the epithelium overlying C57BL/6 mouse and human tonsil tissue as previously described (19,40). HEK293, UPCI SCC90 (provided by Sue Gorlin), and UMSCC84 human cell lines were maintained in 10% fetal bovine serum-Dulbecco modified Eagle medium with 1% penicillin/streptomycin.…”

Section: Methodsmentioning

confidence: 99%

“…To determine whether the E6 PDZBM requirements for AIG also played a role in invasive growth in vivo we also examined an in vivo growth assay that implants the various transduced MTECs back into immune-competent syngeneic C57BL/6 mice. Our past work has found that E6/E7 was sufficient to immortalize but not allow invasive growth of MTECs after reimplantation (19). The addition of Ras v12 to cells expressing E6/E7 allowed invasive tumorigenic growth.…”

Section: E6 Induces Aig In Mtecs Via a Pdz-dependent Mechanismmentioning

confidence: 96%

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The PDZ Binding Motif of Human Papillomavirus Type 16 E6 Induces PTPN13 Loss, Which Allows Anchorage-Independent Growth and Synergizes with Ras for Invasive Growth

Spanos

Hoover

Harris

et al. 2008

J Virol

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118

124

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The human papillomavirus (HPV) oncogene E6 has been shown to perform multiple functions (p53 degradation, telomerase activation, etc.) that play a role in oncogenic transformation. Beyond known E6 functions, an undefined mechanism that allows cellular invasion requires the E6 PDZ binding motif (PDZBM). Here, we show that HPV type 16 (HPV16) E6 interacts with and induces loss of a protein tyrosine phosphatase (PTPN13) in a PDZBM-dependent manner. PTPN13 loss induced either by the presence of E6 or by a short hairpin RNA strategy allows for anchorage-independent growth (AIG) and synergy with a known oncogene, Ras v12 , resulting in invasive growth in vivo. Restoring PTPN13 expression reverses AIG in cells lacking PTPN13. A genomic analysis of colorectal carcinoma has identified an association between PTPN13 loss-of-function mutations and aberrant Ras signaling. Our findings support this correlation and provide methods for further evaluation of the mechanisms by which PTPN13 loss/Ras expression leads to invasive growth, the results of which will be important for treatment of HPV-related and non-HPV cancer.Significant associative evidence supports a role for human papillomavirus type 16 (HPV16) in the carcinogenic progression of at least 25% of head and neck squamous cell cancer (HNSCC) cases (27, 38). In particular, the incidence of HNSCC of the tonsillar region is increasing (18,20,38). The epithelial surfaces surrounding the tonsil (oropharynx) are cancerous in a very high (60%) proportion of cases that are HPV positive, and these cases present with more metastatic and advanced disease states (34, 38) than HPV-negative cases. The incidence of HPV-related HNSCC is also increased in individuals with human immunodeficiency virus/AIDS disease (10). While the data presented in the following studies pertain to HPV-related HNSCC they may also be applicable to cases of HPV-related cervical cancer, which remains the second leading cause of cancer-related death in women. Therefore, understanding the viral mechanisms that lead to cancer will help meet a need for HPV-specific targeted therapy.One of the major HPV viral oncogenes that allow progression to cancer is HPV16 E6. E6 has many potential carcinogenic effects, including telomerase activation and p53 degradation (26, 35). However, an understood mechanism that potentiates malignant progression has been associated with a PDZ (PSD-95, Discs Large, ZO-1) binding motif (PDZBM), a specific amino acid sequence that mediates protein-protein interactions with corresponding PDZ domain-containing proteins. High-risk HPV virus types 16, 18, 31, and 33 possess this binding motif at the E6 C terminus. In addition to this correlative evidence of increased malignant potential in humans, mouse studies demonstrated that PDZBM is required for HPV-related malignancy (37).The studies described below explored the role of the E6 PDZBM in binding and inducing loss of a PDZ domain containing phosphatase PTPN13. PTPN13 is a member of the nonreceptor phosphatases and specifically falls into a cl...

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Section: E6 Induces Aig In Mtecs Via a Pdz-dependent Mechanismmentioning

confidence: 53%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: E6 Induces Aig In Mtecs Via a Pdz-dependent Mechanismmentioning

confidence: 96%

See 3 more Smart Citations

The PDZ Binding Motif of Human Papillomavirus Type 16 E6 Induces PTPN13 Loss, Which Allows Anchorage-Independent Growth and Synergizes with Ras for Invasive Growth

Spanos

Hoover

Harris

et al. 2008

J Virol

Self Cite

118

124

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The Effect of Proteasome Inhibition on p53 Degradation and Proliferation in Tonsil Epithelial Cells

Harris

Anderson²,

Lee

2008

Arch Otolaryngol Head Neck Surg

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Development of an Adenoviral Vaccine Against E6 and E7 Oncoproteins to Prevent Growth of Human Papillomavirus–Positive Cancer

Lee

Anderson²,

Wu³

et al. 2008

Arch Otolaryngol Head Neck Surg

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Immunization with HPV-16 E6/E7 oncoproteins can be an effective method of protecting a host from E6/E7-expressing head and neck squamous cell cancers via generation of a potent immune response. Such a response may be beneficial when combined with traditional treatment such as surgery, chemotherapy, or radiotherapy, thus improving the prognosis and quality of life of patients with HPV-16-associated head and neck squamous cell cancers.

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The Role of Human Papillomavirus 16 E6 in Anchorage-Independent and Invasive Growth of Mouse Tonsil Epithelium

Cited by 74 publications

References 33 publications

The PDZ Binding Motif of Human Papillomavirus Type 16 E6 Induces PTPN13 Loss, Which Allows Anchorage-Independent Growth and Synergizes with Ras for Invasive Growth

The PDZ Binding Motif of Human Papillomavirus Type 16 E6 Induces PTPN13 Loss, Which Allows Anchorage-Independent Growth and Synergizes with Ras for Invasive Growth

The Effect of Proteasome Inhibition on p53 Degradation and Proliferation in Tonsil Epithelial Cells

Development of an Adenoviral Vaccine Against E6 and E7 Oncoproteins to Prevent Growth of Human Papillomavirus–Positive Cancer

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