Loss of RB compromises specific heterochromatin modifications and modulates HP1α dynamics

Siddiqui, Hasan; Fox, Sejal R.; Gunawardena, Ranjaka W.; Knudsen, Erik S.

doi:10.1002/jcp.20913

Cited by 41 publications

(28 citation statements)

References 35 publications

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“…The active nonphosphorylated form of RB is an initiator of SAHF formation that are believed to contribute to stable repression of genes such as cyclin A and stabilization of senescence-associated cell-cycle arrest (46)(47)(48). Furthermore, RB can induce autophagy by repressing E2F1 activity (49), suggesting that RB/E2F1pathway has a dual role in cancer suppression and resistance to cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition

et al. 2013

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Autophagy is frequently activated in radioresistant cancer cells where it provides a cell survival strategy. The mTOR inhibitor rapamycin activates autophagy but paradoxically it also enhances radiosensitivity. In this study, we investigated the mechanisms of these opposing actions in radiation-resistant glioma or parotid carcinoma cells. Radiation treatment transiently enhanced autophagic flux for a period of 72 hours in these cells and treatment with rapamycin or the mTOR inhibitor PP242 potentiated this effect. However, these treatments also increased heterochromatin formation, irreversible growth arrest, and premature senescence, as defined by expression of senescence-associated b-galactosidase activity. This augmentation in radiosensitivity seemed to result from a restoration in the activity of the tumor suppressor RB and a suppression of RB-mediated E2F target genes. In tumor xenografts, we showed that administering rapamycin delayed tumor regrowth after irradiation and increased senescence-associated b-galactosidase staining in the tumor. Our findings suggest that a potent and persistent activation of autophagy by mTOR inhibitors, even in cancer cells where autophagy is occurring, can trigger premature senescence as a method to restore radiosensitivity. Cancer Res; 73(14); 4267-77. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition

et al. 2013

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“…Rb protein was reported to inhibit transcriptional activators via the ability of the E2F complex and recruit Rb to the promoter, thereby inhibiting the activity of other promoter elements (Hiebert et al 1992;Weintraub et al 1992;Siddiqui et al 2007). It was also demonstrated that Rb is a transcriptional repressor of expression of genes transcribed by RNA polymerases I and III (Cavanaugh et al 1995;White et al 1996) …”

Section: Rb-mediated Transcriptional Repression -Molecular Mechanismmentioning

confidence: 94%

Retinoblastoma protein: a central processing unit

Poznic

2009

J Biosci

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The retinoblastoma protein (pRb) is one of the key cell-cycle regulating proteins and its inactivation leads to neoplastic transformation and carcinogenesis. This protein regulates critical G1 -to-S phase transition through interaction with the E2F family of cell-cycle transcription factors repressing transcription of genes required for this cell-cycle check-point transition. Its activity is regulated through network sensing intracellular and extracellular signals which block or permit phosphorylation (inactivation) of the Rb protein. Mechanisms of Rb-dependent cell-cycle control have been widely studied over the past couple of decades. However, recently it was found that pRb also regulates apoptosis through the same interaction with E2F transcription factors and that Rb-E2F complexes play a role in regulating the transcription of genes involved in differentiation and development.

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“…SWI/SNF is a multiprotein complex able to remodel chromatin toward cellular and environmental requirements. In addition to its transcriptional activator functions, it was described also as a transcription repressive element in concert with the SUV39H1/ HP1 complex (18,19). An interaction between ADNP and HP1␣ through the ADNP conserved PXVXL HP1␣ biding motif (11) may explain some of the SWI/SNF-HP1␣ repressive association.…”

Section: Discussionmentioning

confidence: 99%

Activity-dependent Neuroprotective Protein Constitutes a Novel Element in the SWI/SNF Chromatin Remodeling Complex

Mandel¹,

Gozes

2007

Journal of Biological Chemistry

127

111

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Complete deficiency in activity-dependent neuroprotective protein (ADNP), a heterochromatin 1-binding protein, results in dramatic changes in gene expression, neural tube closure defects, and death at gestation day 9 in mice. To further understand the cellular roles played by ADNP, the HEK293 human embryonic kidney cell line that allows efficient transfection with recombinant DNA was used as a model for the identification of ADNP-interacting proteins. Recombinant green fluorescent protein (GFP)-ADNP was localized to cell nuclei. When nuclear extracts were subjected to immunoprecipitation with specific GFP antibodies followed by polyacrylamide gel electrophoresis, several minor protein bands were observed in addition to GFP-ADNP. In-gel protein digests followed by mass spectrometry identified BRG1, BAF250a, and BAF170, all components of the SWI/SNF (mating type switching/sucrose nonfermenting) chromatin remodeling complex, as proteins that co-immunoprecipitate with ADNP. These results were verified utilizing BRG1 antibodies. ADNP short hairpin RNA down-regulation resulted in microtubule reorganization and changes in cell morphology including reduction in cell process formation and cell number. These morphological changes are closely associated with the SWI/SNF complex multifunctionality. Taken together, the current study uncovers a molecular basis for the essential function of the ADNP gene and protein.Activity-dependent neuroprotective protein (ADNP 3 (1)) was originally discovered as a gene product associated with neuroprotection/neuroglia interactions (2). ADNP immunoreactivity was shown to localize to the astrocyte nucleus as well as to the cytoplasm and to the extracellular space, where the protein enhances neuronal survival (3, 4). Further studies suggested very high gene conservation in mammals including humans, increased expression in malignant cells, and close association with cellular survival (5). In the mature brain, ADNP expression was modulated by injury, suggesting a potential protective effect for the protein in vivo (6, 7). Additionally, ADNP expression shows sexual dichotomy and is modulated during the estrous cycle in the arcuate nucleus of the hypothalamus (8) and in the vagina (9), suggesting a potential neurotrophic/plasticity-associated effect for the protein.Importantly, complete deficiency in ADNP results in neural tube closure defects and death at gestation day 9 in mice (10). ADNP-deficient embryos exhibit dramatic increases in gene transcripts associated with lipid metabolism coupled to a reduction in organogenesis/neurogenesis related transcripts (11). In pluripotent P19 cells, ADNP was shown to interact with specific chromatin regions in the neuro-differentiated state, which was associated with binding to heterochromatin protein 1 (11). To further understand ADNP function, the HEK293 human embryonic kidney cell line that allows efficient transfection with recombinant DNA was used as a model for the identification of ADNP-interacting proteins and cellular function, suggesting that ADN...

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Loss of RB compromises specific heterochromatin modifications and modulates HP1α dynamics

Cited by 41 publications

References 35 publications

Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition

Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition

Retinoblastoma protein: a central processing unit

Activity-dependent Neuroprotective Protein Constitutes a Novel Element in the SWI/SNF Chromatin Remodeling Complex

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