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 Cyclin A Is a Functional Target of Retinoblastoma Tumor Suppressor Protein-mediated Cell Cycle Arrest

1999 ◽  
Vol 274 (39) ◽  
pp. 27632-27641 ◽  
Author(s):  
Karen E. Knudsen ◽  
Anne F. Fribourg ◽  
Matthew W. Strobeck ◽  
Jean-Marie Blanchard ◽  
Erik S. Knudsen
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Cyclin A ◽  
Tumor Suppressor Protein ◽  
Retinoblastoma Tumor Suppressor Protein ◽  
Retinoblastoma Tumor Suppressor ◽  
Cycle Arrest ◽  
Retinoblastoma Tumor

scholarly journals Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma

2004 ◽  
Vol 167 (5) ◽  
pp. 925-934 ◽  
Author(s):  
David M. Thomas ◽  
Sandra A. Johnson ◽  
Natalie A. Sims ◽  
Melanie K. Trivett ◽  
John L. Slavin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Osteoblast Differentiation ◽  
Ectopic Expression ◽  
Osteosarcoma Cell ◽  
Cell Cycle Exit ◽  
Retinoblastoma Tumor Suppressor ◽  
Cycle Arrest ◽  
Permanent Cell ◽  
Retinoblastoma Tumor

The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2, a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27KIP1, thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.

scholarly journals Stabilization of the Retinoblastoma Protein by A-Type Nuclear Lamins Is Required for INK4A-Mediated Cell Cycle Arrest

2006 ◽  
Vol 26 (14) ◽  
pp. 5360-5372 ◽  
Author(s):  
Ryan T. Nitta ◽  
Samantha A. Jameson ◽  
Brian A. Kudlow ◽  
Lindus A. Conlan ◽  
Brian K. Kennedy
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Cell Cycle Control ◽  
Retinoblastoma Protein ◽  
Lamin A ◽  
Nuclear Lamins ◽  
Cycle Arrest ◽  
Functional Consequences ◽  
Mandibuloacral Dysplasia

ABSTRACT Mutations in the LMNA gene, which encodes all A-type lamins, including lamin A and lamin C, cause a variety of tissue-specific degenerative diseases termed laminopathies. Little is known about the pathogenesis of these disorders. Previous studies have indicated that A-type lamins interact with the retinoblastoma protein (pRB). Here we probe the functional consequences of this association and further examine links between nuclear structure and cell cycle control. Since pRB is required for cell cycle arrest by p16ink4a, we tested the responsiveness of multiple lamin A/C-depleted cell lines to overexpression of this CDK inhibitor and tumor suppressor. We find that the loss of A-type lamin expression results in marked destabilization of pRB. This reduction in pRB renders cells resistant to p16ink4a-mediated G1 arrest. Reintroduction of lamin A, lamin C, or pRB restores p16ink4a-responsiveness to Lmna −/− cells. An array of lamin A mutants, representing a variety of pathologies as well as lamin A processing mutants, was introduced into Lmna −/− cells. Of these, a mutant associated with mandibuloacral dysplasia (MAD R527H), as well as two lamin A processing mutants, but not other disease-associated mutants, failed to restore p16ink4a responsiveness. Although our findings do not rule out links between altered pRB function and laminopathies, they fail to support such an assertion. These findings do link lamin A/C to the functional activation of a critical tumor suppressor pathway and further the possibility that somatic mutations in LMNA contribute to tumor progression.

scholarly journals Destabilization of the Retinoblastoma Tumor Suppressor by Human Papillomavirus Type 16 E7 Is Not Sufficient To Overcome Cell Cycle Arrest in Human Keratinocytes

2001 ◽  
Vol 75 (15) ◽  
pp. 6737-6747 ◽  
Author(s):  
Anna-Marija Helt ◽  
Denise A. Galloway
Keyword(s):  
Cell Cycle ◽  
Human Papillomavirus ◽  
Cell Cycle Arrest ◽  
Human Papillomavirus Type 16 ◽  
Cycle Arrest ◽  
C Terminus ◽  
Conserved Region ◽  
Retinoblastoma Tumor ◽  
Lxcxe Motif

ABSTRACT The E7 oncoprotein of human papillomavirus type 16 promotes cell proliferation in the presence of antiproliferative signals. Mutagenesis of E7 has revealed that this activity requires three regions, conserved regions 1 and 2 and a C-terminal zinc finger. Binding to the retinoblastoma tumor repressor (Rb) through an LxCxE motif in conserved region 2 is necessary, but not sufficient, for E7 to induce proliferation. We tested the hypothesis that binding to Rb is not sufficient because conserved region 1 and/or the C terminus are required for E7 to functionally inactivate Rb and thus induce proliferation. One mechanism proposed for how E7 inactivates Rb is by blocking Rb-E2F binding. Either conserved region 1 or the C terminus was necessary, in combination with the LxCxE motif, for E7 to block Rb-E2F binding in vitro. While all full-length E7 proteins with mutations outside of the LxCxE motif inhibited Rb-E2F binding, some failed to abrogate cell cycle arrest, demonstrating that blocking Rb-E2F binding is not sufficient for abrogating antiproliferative signals. Another mechanism proposed for how E7 inactivates Rb is by promoting the destabilization of Rb protein. Mutations in conserved region 1 or the LxCxE motif prevented E7 from reducing the half-life of Rb. Though no specific C-terminal residues of E7 were essential for destabilizing Rb, a novel class of mutations that uncouple the destabilization of Rb from the deregulation of keratinocyte proliferation was discovered. Destabilization of Rb correlated with the abrogation of Rb-induced quiescence but was not sufficient for overriding DNA damage-induced cell cycle arrest or for increasing keratinocyte life span. Finally, the same regions of E7 required for destabilizing Rb were required for reducing p107 and p130 levels. Together, these results suggest that inactivation of all three Rb family members is not sufficient to deregulate keratinocyte cell cycle control.

scholarly journals Tumor Suppressor Inactivation in the Pathogenesis of Adult T-Cell Leukemia

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Christophe Nicot
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Tumor Suppressors ◽  
Epigenetic Mechanisms ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Cycle Arrest

Tumor suppressor functions are essential to control cellular proliferation, to activate the apoptosis or senescence pathway to eliminate unwanted cells, to link DNA damage signals to cell cycle arrest checkpoints, to activate appropriate DNA repair pathways, and to prevent the loss of adhesion to inhibit initiation of metastases. Therefore, tumor suppressor genes are indispensable to maintaining genetic and genomic integrity. Consequently, inactivation of tumor suppressors by somatic mutations or epigenetic mechanisms is frequently associated with tumor initiation and development. In contrast, reactivation of tumor suppressor functions can effectively reverse the transformed phenotype and lead to cell cycle arrest or death of cancerous cells and be used as a therapeutic strategy. Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoproliferative disease associated with infection of CD4 T cells by the Human T-cell Leukemia Virus Type 1 (HTLV-I). HTLV-I-associated T-cell transformation is the result of a multistep oncogenic process in which the virus initially induces chronic T-cell proliferation and alters cellular pathways resulting in the accumulation of genetic defects and the deregulated growth of virally infected cells. This review will focus on the current knowledge of the genetic and epigenetic mechanisms regulating the inactivation of tumor suppressors in the pathogenesis of HTLV-I.

scholarly journals ei24, a p53 Response Gene Involved in Growth Suppression and Apoptosis

2000 ◽  
Vol 20 (1) ◽  
pp. 233-241 ◽  
Author(s):  
Zhengming Gu ◽  
Cathy Flemington ◽  
Thomas Chittenden ◽  
Gerard P. Zambetti
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Apoptotic Cell ◽  
Functional Characterization ◽  
Growth Control ◽  
P53 Tumor Suppressor ◽  
Cycle Arrest ◽  
P53 Response

ABSTRACT DNA damage and/or hyperproliferative signals activate the wild-type p53 tumor suppressor protein, which induces a G1 cell cycle arrest or apoptosis. Although the mechanism of p53-mediated cell cycle arrest is fairly well defined, the p53-dependent pathway regulating apoptosis is poorly understood. Here we report the functional characterization of murine ei24 (also known asPIG8), a gene directly regulated by p53, whose overexpression negatively controls cell growth and induces apoptotic cell death. Ectopic ei24 expression markedly inhibits cell colony formation, induces the morphological features of apoptosis, and reduces the number of β-galactosidase-marked cells, which is efficiently blocked by coexpression of Bcl-XL. Theei24/PIG8 gene is localized on human chromosome 11q23, a region frequently altered in human cancers. These results suggest that ei24 may play an important role in negative cell growth control by functioning as an apoptotic effector of p53 tumor suppressor activities.

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.

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