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LincRNA-p21 acts as a mediator of ING1b-induced apoptosis.

Tran UM, Rajarajacholan U, Soh J, Kim TS, Thalappilly S, Sensen CW, Riabowol K - Cell Death Dis (2015)

Bottom Line: We found that this function of lincRNA-p21 is conserved in human cell models.However, their effects become more additive under conditions of stress.Surprisingly, deletion of the ING1b plant homeodomain, which allows it to bind histones and regulate chromatin structure, did not alter regulation of lincRNA-p21.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, and Oncology, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1 Alberta, Canada.

ABSTRACT
ING1b is a tumor suppressor that affects transcription, cell cycle control and apoptosis. ING1b is deregulated in disease, and its activity is closely linked to that of p53. In addition to regulating protein-coding genes, we found that ING1b also influences the expression of large intergenic non-coding RNAs (lincRNAs). In particular, lincRNA-p21 was significantly induced after DNA-damage stress or by ING1b overexpression. Furthermore, lincRNA-p21 expression in response to DNA damage was significantly attenuated in cells lacking ING1b. LincRNA-p21 is also a target of p53 and can trigger apoptosis in mouse cell models. We found that this function of lincRNA-p21 is conserved in human cell models. Moreover, ING1b and p53 could function independently to influence lincRNA-p21 expression. However, their effects become more additive under conditions of stress. In particular, ING1b regulates lincRNA-p21 levels by binding to its promoter and is required for induction of lincRNA-p21 by p53. The ability of ING1b to cause apoptosis is also impaired in the absence of lincRNA-p21. Surprisingly, deletion of the ING1b plant homeodomain, which allows it to bind histones and regulate chromatin structure, did not alter regulation of lincRNA-p21. Our findings suggest that ING1b induces lincRNA-p21 expression independently of histone 3 lysine 4 trimethylation mark recognition and that lincRNA-p21 functions downstream of ING1b. Thus, regulation at the level of lincRNA-p21 may represent the point at which ING1b and p53 pathways converge to induce apoptosis under specific stress conditions.

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Related in: MedlinePlus

A schematic representation of the functional interdependence between ING1b and p53 in DNA-damage induction of apoptosis. Damage to DNA or to other macromolecules initiates a stress response that activates ING1b by phosphoinositide binding and stabilizes p53 by ING1-dependent and -independent pathways that inhibit p53 ubiquitination. ING1 and p53 then converge at the level of lincRNA-p21, inducing an increase in its expression. Subsequently, lincRNA-p21 reinforces transcriptional changes by p53 and ING1b that regulate Bax and Bak expression, which then converge with both p53 and ING1b at the mitochondrial membrane to promote release of cytochrome C. Variable amounts of ING1b and p53 localize to the mitochondrial membrane, depending upon cell type. Cyt C then induces assembly of Apaf 1 into active apoptosomes, initiating the dimerization and processing of procaspase 9 on the apoptosome. Active caspase 9 then cleaves procaspase 3 to produce active caspase 3 and the initiation of proteolysis inducing apoptosis
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fig8: A schematic representation of the functional interdependence between ING1b and p53 in DNA-damage induction of apoptosis. Damage to DNA or to other macromolecules initiates a stress response that activates ING1b by phosphoinositide binding and stabilizes p53 by ING1-dependent and -independent pathways that inhibit p53 ubiquitination. ING1 and p53 then converge at the level of lincRNA-p21, inducing an increase in its expression. Subsequently, lincRNA-p21 reinforces transcriptional changes by p53 and ING1b that regulate Bax and Bak expression, which then converge with both p53 and ING1b at the mitochondrial membrane to promote release of cytochrome C. Variable amounts of ING1b and p53 localize to the mitochondrial membrane, depending upon cell type. Cyt C then induces assembly of Apaf 1 into active apoptosomes, initiating the dimerization and processing of procaspase 9 on the apoptosome. Active caspase 9 then cleaves procaspase 3 to produce active caspase 3 and the initiation of proteolysis inducing apoptosis

Mentions: The observations noted above indicate that both ING1 and p53 contribute approximately equally to the induction of lincRNA-p21. We found that ING1b bound the lincRNA-p21 promoter and drove the expression of reporter constructs, whereas a previous study noted the presence of p53-binding sites in the same region, consistent with ING1 and p53 jointly inducing lincRNA-p21 transcription. A model highlighting this relationship is shown in Figure 8. Knockdown of lincRNA-p21 also showed that it contributed significantly to ING1b-induced apoptosis. However, the following two observations do not fit simply into this model: ING1b binding to the lincRNA-p21 promoter occurs most efficiently when p53 is lacking in the cell suggesting that ING1b and/or p53 also affect lincRNA-p21 expression by mechanisms other than those requiring promoter binding. In addition, the PHD region of ING1, which binds chromatin at HeK4Me3 marks, is not required for induction, further suggesting that ING1 contributes to induction of lincRNA-p21 by means other than affecting nucleosome structure through binding H3K4Me3. ING1b is not a transcriptional target of p5332 but rather appears to protect p53 from degradation15, 35 to enhance its activity. This represents another mechanism by which ING1b and p53 may interact to increase levels of lincRNA-p21, which might also explain their convergence of function in inducing apoptosis, an observation made independently in previous studies.1, 10, 11, 12


LincRNA-p21 acts as a mediator of ING1b-induced apoptosis.

Tran UM, Rajarajacholan U, Soh J, Kim TS, Thalappilly S, Sensen CW, Riabowol K - Cell Death Dis (2015)

A schematic representation of the functional interdependence between ING1b and p53 in DNA-damage induction of apoptosis. Damage to DNA or to other macromolecules initiates a stress response that activates ING1b by phosphoinositide binding and stabilizes p53 by ING1-dependent and -independent pathways that inhibit p53 ubiquitination. ING1 and p53 then converge at the level of lincRNA-p21, inducing an increase in its expression. Subsequently, lincRNA-p21 reinforces transcriptional changes by p53 and ING1b that regulate Bax and Bak expression, which then converge with both p53 and ING1b at the mitochondrial membrane to promote release of cytochrome C. Variable amounts of ING1b and p53 localize to the mitochondrial membrane, depending upon cell type. Cyt C then induces assembly of Apaf 1 into active apoptosomes, initiating the dimerization and processing of procaspase 9 on the apoptosome. Active caspase 9 then cleaves procaspase 3 to produce active caspase 3 and the initiation of proteolysis inducing apoptosis
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4385912&req=5

fig8: A schematic representation of the functional interdependence between ING1b and p53 in DNA-damage induction of apoptosis. Damage to DNA or to other macromolecules initiates a stress response that activates ING1b by phosphoinositide binding and stabilizes p53 by ING1-dependent and -independent pathways that inhibit p53 ubiquitination. ING1 and p53 then converge at the level of lincRNA-p21, inducing an increase in its expression. Subsequently, lincRNA-p21 reinforces transcriptional changes by p53 and ING1b that regulate Bax and Bak expression, which then converge with both p53 and ING1b at the mitochondrial membrane to promote release of cytochrome C. Variable amounts of ING1b and p53 localize to the mitochondrial membrane, depending upon cell type. Cyt C then induces assembly of Apaf 1 into active apoptosomes, initiating the dimerization and processing of procaspase 9 on the apoptosome. Active caspase 9 then cleaves procaspase 3 to produce active caspase 3 and the initiation of proteolysis inducing apoptosis
Mentions: The observations noted above indicate that both ING1 and p53 contribute approximately equally to the induction of lincRNA-p21. We found that ING1b bound the lincRNA-p21 promoter and drove the expression of reporter constructs, whereas a previous study noted the presence of p53-binding sites in the same region, consistent with ING1 and p53 jointly inducing lincRNA-p21 transcription. A model highlighting this relationship is shown in Figure 8. Knockdown of lincRNA-p21 also showed that it contributed significantly to ING1b-induced apoptosis. However, the following two observations do not fit simply into this model: ING1b binding to the lincRNA-p21 promoter occurs most efficiently when p53 is lacking in the cell suggesting that ING1b and/or p53 also affect lincRNA-p21 expression by mechanisms other than those requiring promoter binding. In addition, the PHD region of ING1, which binds chromatin at HeK4Me3 marks, is not required for induction, further suggesting that ING1 contributes to induction of lincRNA-p21 by means other than affecting nucleosome structure through binding H3K4Me3. ING1b is not a transcriptional target of p5332 but rather appears to protect p53 from degradation15, 35 to enhance its activity. This represents another mechanism by which ING1b and p53 may interact to increase levels of lincRNA-p21, which might also explain their convergence of function in inducing apoptosis, an observation made independently in previous studies.1, 10, 11, 12

Bottom Line: We found that this function of lincRNA-p21 is conserved in human cell models.However, their effects become more additive under conditions of stress.Surprisingly, deletion of the ING1b plant homeodomain, which allows it to bind histones and regulate chromatin structure, did not alter regulation of lincRNA-p21.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, and Oncology, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1 Alberta, Canada.

ABSTRACT
ING1b is a tumor suppressor that affects transcription, cell cycle control and apoptosis. ING1b is deregulated in disease, and its activity is closely linked to that of p53. In addition to regulating protein-coding genes, we found that ING1b also influences the expression of large intergenic non-coding RNAs (lincRNAs). In particular, lincRNA-p21 was significantly induced after DNA-damage stress or by ING1b overexpression. Furthermore, lincRNA-p21 expression in response to DNA damage was significantly attenuated in cells lacking ING1b. LincRNA-p21 is also a target of p53 and can trigger apoptosis in mouse cell models. We found that this function of lincRNA-p21 is conserved in human cell models. Moreover, ING1b and p53 could function independently to influence lincRNA-p21 expression. However, their effects become more additive under conditions of stress. In particular, ING1b regulates lincRNA-p21 levels by binding to its promoter and is required for induction of lincRNA-p21 by p53. The ability of ING1b to cause apoptosis is also impaired in the absence of lincRNA-p21. Surprisingly, deletion of the ING1b plant homeodomain, which allows it to bind histones and regulate chromatin structure, did not alter regulation of lincRNA-p21. Our findings suggest that ING1b induces lincRNA-p21 expression independently of histone 3 lysine 4 trimethylation mark recognition and that lincRNA-p21 functions downstream of ING1b. Thus, regulation at the level of lincRNA-p21 may represent the point at which ING1b and p53 pathways converge to induce apoptosis under specific stress conditions.

Show MeSH
Related in: MedlinePlus