scholarly journals Conserved Region 3 of Human Papillomavirus 16 E7 Contributes to Deregulation of the Retinoblastoma Tumor Suppressor

2012 ◽  
Vol 86 (24) ◽  
pp. 13313-13323 ◽  
Author(s):  
B. Todorovic ◽  
K. Hung ◽  
P. Massimi ◽  
N. Avvakumov ◽  
F. A. Dick ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Tumor Suppressor ◽  
Human Papillomavirus 16 ◽  
Retinoblastoma Tumor Suppressor ◽  
Conserved Region ◽  
Retinoblastoma Tumor

scholarly journals Degradation of the Retinoblastoma Tumor Suppressor by the Human Papillomavirus Type 16 E7 Oncoprotein Is Important for Functional Inactivation and Is Separable from Proteasomal Degradation of E7

2001 ◽  
Vol 75 (16) ◽  
pp. 7583-7591 ◽  
Author(s):  
Sonia L. Gonzalez ◽  
Matt Stremlau ◽  
Xi He ◽  
John R. Basile ◽  
Karl Münger
Keyword(s):  
Human Papillomavirus ◽  
Tumor Suppressor ◽  
Selection Process ◽  
State Level ◽  
Proteasomal Degradation ◽  
Biological Indicator ◽  
26S Proteasome ◽  
Amino Terminal ◽  
Retinoblastoma Tumor Suppressor ◽  
Retinoblastoma Tumor

ABSTRACT The steady-state level and metabolic half-life of retinoblastoma tumor suppressor protein pRB are decreased in cells that express high-risk human papillomavirus (HPV) E7 proteins. Here we show that pRB degradation is a direct activity of E7 and does not reflect a property of cell lines acquired during the selection process for E7 expression. An amino-terminal domain of E7 that does not directly contribute to pRB binding but is required for transformation is also necessary for E7-mediated pRB degradation. Treatment with inhibitors of the 26S proteasome not only blocks E7-mediated pRB degradation but also causes the stabilization of E7. Mutagenic analyses, however, reveal that the processes of proteasomal degradation of E7 and pRB are not linked processes. HPV type 16 E7 also targets the pRB-related proteins p107 and p130 for destabilization by a proteasome-dependent mechanism. Using the SAOS2 flat-cell assay as a biological indicator for pRB function, we demonstrate that pRB degradation, not solely binding, is important for the E7-induced inactivation of pRB.

scholarly journals The Mus musculus Papillomavirus Type 1 E7 Protein Binds to the Retinoblastoma Tumor Suppressor: Implications for Viral Pathogenesis

mBio ◽  
2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Tao Wei ◽  
Miranda Grace ◽  
Aayushi Uberoi ◽  
James C. Romero-Masters ◽  
Denis Lee ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Tumor Suppressor ◽  
Squamous Cell ◽  
Mus Musculus ◽  
Viral Pathogenesis ◽  
Squamous Cell Carcinomas ◽  
Papillomavirus Infections ◽  
Retinoblastoma Tumor Suppressor ◽  
Retinoblastoma Tumor

Papillomavirus infections cause a variety of epithelial hyperplastic lesions, or warts. While most warts are benign, some papillomaviruses cause lesions that can progress to squamous cell carcinomas, and approximately 5% of all human cancers are caused by human papillomavirus (HPV) infections.

scholarly journals The Retinoblastoma Tumor Suppressor Is Required for the NUP98-HOXA9-Induced Aberrant Nuclear Envelope Phenotype

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2851
Author(s):  
Marcela Vaz ◽  
Birthe Fahrenkrog
Keyword(s):  
Tumor Suppressor ◽  
Nuclear Envelope ◽  
Fusion Proteins ◽  
Nuclear Architecture ◽  
Nuclear Lamina ◽  
Dependent Manner ◽  
Morphological Alterations ◽  
Human Papillomavirus 16 ◽  
Retinoblastoma Tumor Suppressor ◽  
Retinoblastoma Tumor

Chromosomal translocations involving the nucleoporin NUP98 gene are recurrently identified in leukemia; yet, the cellular defects accompanying NUP98 fusion proteins are poorly characterized. NUP98 fusions cause changes in nuclear and nuclear envelope (NE) organization, in particular, in the nuclear lamina and the lamina associated polypeptide 2α (LAP2α), a regulator of the tumor suppressor retinoblastoma protein (RB). We demonstrate that, for NUP98-HOXA9 (NHA9), the best-studied NUP98 fusion protein, its effect(s) on nuclear architecture largely depend(s) on RB. Morphological alterations caused by the expression of NHA9 are largely diminished in the absence of RB, both in human cells expressing the human papillomavirus 16 E7 protein and in mouse embryonic fibroblasts lacking RB. We further show that NHA9 expression associates with distinct histone modification. Moreover, the pattern of trimethylation of histone H3 lysine-27 is affected by NHA9, again in an RB-dependent manner. Our results pinpoint to an unexpected interplay between NUP98 fusion proteins and RB, which may contribute to leukemogenesis.

scholarly journals Inactivation of both the Retinoblastoma Tumor Suppressor and p21 by the Human Papillomavirus Type 16 E7 Oncoprotein Is Necessary To Inhibit Cell Cycle Arrest in Human Epithelial Cells

2002 ◽  
Vol 76 (20) ◽  
pp. 10559-10568 ◽  
Author(s):  
Anna-Marija Helt ◽  
Jens Oliver Funk ◽  
Denise A. Galloway
Keyword(s):  
Cell Cycle ◽  
Human Papillomavirus ◽  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Cell Cycle Arrest ◽  
Cell Cycle Control ◽  
E7 Oncoprotein ◽  
Retinoblastoma Tumor Suppressor ◽  
Cycle Arrest ◽  
Retinoblastoma Tumor

ABSTRACT The human papillomavirus (HPV) type 16 E7 oncoprotein must inactivate the retinoblastoma tumor suppressor (Rb) pathway to bypass G1 arrest. However, E7 C-terminal mutants that were able to inactivate Rb were unable to bypass DNA damage-induced G1 arrest and keratinocyte senescence, suggesting that the E7 C terminus may target additional G1 regulators. The E7 C-terminal mutant proteins E7 CVQ68-70AAA and E7 Δ79-83 (deletion of positions 79 through 83) were further tested in several models of cell cycle arrest associated with elevated levels of p21. C-terminal mutations rendered E7 unable to induce S phase and endoreduplication in differentiated keratinocytes and rendered it less efficient in delaying senescence of human mammary epithelial cells. Interestingly, when cell cycle arrest was induced with a peptide form of p21, the E7 C-terminal mutants were deficient in overcoming arrest, whereas a mutant defective in Rb binding was competent in inhibiting G1 arrest. These results suggest that the inactivation of both p21 and Rb by E7 contributes to subversion of cell cycle control in normal human epithelia but that neither p21 nor Rb inactivation alone is sufficient.

scholarly journals Human Papillomavirus Type 16 E7 Oncoprotein Associates with the Cullin 2 Ubiquitin Ligase Complex, Which Contributes to Degradation of the Retinoblastoma Tumor Suppressor

2007 ◽  
Vol 81 (18) ◽  
pp. 9737-9747 ◽  
Author(s):  
KyungWon Huh ◽  
Xiaobo Zhou ◽  
Hiroyuki Hayakawa ◽  
Je-Yoel Cho ◽  
Towia A. Libermann ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Tumor Suppressor ◽  
Ubiquitin Ligase ◽  
Ectopic Expression ◽  
Human Papillomavirus Type 16 ◽  
Retinoblastoma Tumor Suppressor ◽  
Ubiquitin Ligase Complex ◽  
Retinoblastoma Tumor ◽  
Cullin 2

ABSTRACT Human papillomavirus type 16 (HPV16) and other high-risk HPVs are etiologically linked to the development of cervical carcinomas and contribute to a number of other tumors of the anogenital tract, as well as oral cancers. The high-risk HPV E6 and E7 oncoproteins are consistently expressed in cervical cancer cells and are necessary for the induction and maintenance of the transformed phenotype. An important aspect of HPV16 E7's oncogenic activities is destabilization of the retinoblastoma tumor suppressor (pRB) through a ubiquitin/proteasome-dependent mechanism, although the exact molecular mechanism is unknown. Here, we report that HPV16 E7 is associated with an enzymatically active cullin 2 ubiquitin ligase complex and that the HPV16 E7/pRB complex contains cullin 2. Depletion of cullin 2 by RNA interference causes increased steady-state levels and stability of pRB in HPV16 E7-expressing cells, and ectopic expression of HPV16 E7 and the cullin 2 complex leads to pRB ubiquitination in vivo. Hence, we propose that the HPV16 E7-associated cullin 2 ubiquitin ligase complex contributes to aberrant degradation of the pRB tumor suppressor in HPV16 E7-expressing cells.

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