Deregulated cell cycle control in lens epithelial cells by expression of inhibitors of tumor suppressor function

Abstract The Inhibitor of Growth (ING) gene family is a group of tumor suppressor genes that play important roles in cell cycle control, senescence, DNA repair, cell proliferation, and apoptosis. However, inactivation and downregulation of these proteins have been related in some neoplasms. The present study aimed to evaluate the immunohistochemical profiles of ING3 and ING4 proteins in a series of benign epithelial odontogenic lesions. Methods: The sample comprised of 20 odontogenic keratocysts (OKC), 20 ameloblastomas (AM), and 15 adenomatoid odontogenic tumors (AOT) specimens. Nuclear and cytoplasmic immunolabeling of ING3 and ING4 were semi-quantitatively evaluated in epithelial cells of the odontogenic lesions, according to the percentage of immunolabelled cells in each case. Descriptive and statistics analysis were computed, and the p-value was set at 0.05. Results: No statistically significant differences were found in cytoplasmic and nuclear ING3 immunolabeling among the studied lesions. In contrast, AOTs presented higher cytoplasmic and nuclear ING4 labeling compared to AMs (cytoplasmic p-value = 0.01; nuclear p-value < 0.001) and OKCs (nuclear p-value = 0.007). Conclusion: ING3 and ING4 protein downregulation may play an important role in the initiation and progression of more aggressive odontogenic lesions, such as AMs and OKCs.

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Cell Cycle Arrest and Repression of Cyclin D1 Transcription by INI1/hSNF5

Molecular and Cellular Biology ◽

10.1128/mcb.22.16.5975-5988.2002 ◽

2002 ◽

Vol 22 (16) ◽

pp. 5975-5988 ◽

Cited By ~ 172

Author(s):

Zhi-Kai Zhang ◽

Kelvin P. Davies ◽

Jeffrey Allen ◽

Liang Zhu ◽

Richard G. Pestell ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Cyclin D1 ◽

Cell Cycle Arrest ◽

Cell Formation ◽

Dependent Manner ◽

Tumor Suppressor Function ◽

Suppressor Function ◽

Cycle Arrest ◽

Flat Cell

ABSTRACT INI1/hSNF5 is a component of the ATP-dependent chromatin remodeling hSWI/SNF complex and a tumor suppressor gene of aggressive pediatric atypical teratoid and malignant rhabdoid tumors (AT/RT). To understand the molecular mechanisms underlying its tumor suppressor function, we studied the effect of reintroduction of INI1/hSNF5 into AT/RT-derived cell lines such as MON that carry biallelic deletions of the INI1/hSNF5 locus. We demonstrate that expression of INI1/hSNF5 causes G0-G1 arrest and flat cell formation in these cells. In addition, INI1/hSNF5 repressed transcription of cyclin D1 gene in MON, in a histone deacetylase (HDAC)-dependent manner. Chromatin immunoprecipitation studies revealed that INI1/hSNF5 was directly recruited to the cyclin D1 promoter and that its binding correlated with recruitment of HDAC1 and deacetylation of histones at the promoter. Analysis of INI1/hSNF5 truncations indicated that cyclin D1 repression and flat cell formation are tightly correlated. Coexpression of cyclin D1 from a heterologous promoter in MON was sufficient to eliminate the INI1-mediated flat cell formation and cell cycle arrest. Furthermore, cyclin D1 was overexpressed in AT/RT tumors. Our data suggest that one of the mechanisms by which INI1/hSNF5 exerts its tumor suppressor function is by mediating the cell cycle arrest due to the direct recruitment of HDAC activity to the cyclin D1 promoter thereby causing its repression and G0-G1 arrest. Repression of cyclin D1 gene expression may serve as a useful strategy to treat AT/RT.

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PRMT5 is required for cell-cycle progression and p53 tumor suppressor function

Nucleic Acids Research ◽

10.1093/nar/gkp516 ◽

2009 ◽

Vol 37 (15) ◽

pp. 4965-4976 ◽

Cited By ~ 98

Author(s):

A. Scoumanne ◽

J. Zhang ◽

X. Chen

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Cell Cycle Progression ◽

Tumor Suppressor Function ◽

Cycle Progression ◽

P53 Tumor Suppressor ◽

Suppressor Function

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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

Journal of Virology ◽

10.1128/jvi.76.20.10559-10568.2002 ◽

2002 ◽

Vol 76 (20) ◽

pp. 10559-10568 ◽

Cited By ~ 67

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.

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O6-methylguanine–induced transcriptional mutagenesis reduces p53 tumor-suppressor function

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1721764115 ◽

2018 ◽

Vol 115 (18) ◽

pp. 4731-4736 ◽

Cited By ~ 9

Author(s):

Monika Ezerskyte ◽

João A. Paredes ◽

Stefano Malvezzi ◽

John A. Burns ◽

Geoffrey P. Margison ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Protein Function ◽

Mammalian Cells ◽

Cell Cycle Checkpoint ◽

Dominant Negative ◽

Tumor Suppressor Function ◽

Suppressor Function ◽

Transcriptional Mutagenesis ◽

The Impact

Altered protein function due to mutagenesis plays an important role in disease development. This is perhaps most evident in tumorigenesis and the associated loss or gain of function of tumor-suppressor genes and oncogenes. The extent to which lesion-induced transcriptional mutagenesis (TM) influences protein function and its contribution to the development of disease is not well understood. In this study, the impact of O6-methylguanine on the transcription fidelity of p53 and the subsequent effects on the protein’s function as a regulator of cell death and cell-cycle arrest were examined in human cells. Levels of TM were determined by RNA-sequencing. In cells with active DNA repair, misincorporation of uridine opposite the lesion occurred in 0.14% of the transcripts and increased to 14.7% when repair by alkylguanine–DNA alkyltransferase was compromised. Expression of the dominant-negative p53 R248W mutant due to TM significantly reduced the transactivation of several established p53 target genes that mediate the tumor-suppressor function, including CDKN1A (p21) and BBC3 (PUMA). This resulted in deregulated signaling through the retinoblastoma protein and loss of G1/S cell-cycle checkpoint function. In addition, we observed impaired activation of apoptosis coupled to the reduction of the tumor-suppressor functions of p53. Taking these findings together, this work provides evidence that TM can induce phenotypic changes in mammalian cells that have important implications for the role of TM in tumorigenesis.

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p190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity

The Journal of Cell Biology ◽

10.1083/jcb.201710058 ◽

2018 ◽

Vol 217 (9) ◽

pp. 3183-3201 ◽

Cited By ~ 8

Author(s):

Scott R. Frank ◽

Clemens P. Köllmann ◽

Phi Luong ◽

Giorgio G. Galli ◽

Lihua Zou ◽

...

Keyword(s):

Tumor Suppressor ◽

Epithelial Cells ◽

Nuclear Translocation ◽

Hippo Pathway ◽

Contact Inhibition ◽

Tumor Suppressor Function ◽

Suppressor Function ◽

Expression Of Genes ◽

P190 Rhogap ◽

The Hippo Pathway

ARHGAP35 encoding p190A RhoGAP is a cancer-associated gene with a mutation spectrum suggestive of a tumor-suppressor function. In this study, we demonstrate that loss of heterozygosity for ARHGAP35 occurs in human tumors. We sought to identify tumor-suppressor capacities for p190A RhoGAP (p190A) and its paralog p190B in epithelial cells. We reveal an essential role for p190A and p190B to promote contact inhibition of cell proliferation (CIP), a function that relies on RhoGAP activity. Unbiased mRNA sequencing analyses establish that p190A and p190B modulate expression of genes associated with the Hippo pathway. Accordingly, we determine that p190A and p190B induce CIP by repressing YAP–TEAD-regulated gene transcription through activation of LATS kinases and inhibition of the Rho–ROCK pathway. Finally, we demonstrate that loss of a single p190 paralog is sufficient to elicit nuclear translocation of YAP and perturb CIP in epithelial cells cultured in Matrigel. Collectively, our data reveal a novel mechanism consistent with a tumor-suppressor function for ARHGAP35.

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