A function of p21 during promyelocytic leukemia cell differentiation independent of CDK inhibition and cell cycle arrest

Casini, Tullia; Pelicci, Pier Giuseppe

doi:10.1038/sj.onc.1202630

Cited by 86 publications

(58 citation statements)

References 42 publications

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“…The Kaplan-Meier survival curve of (a) nude mice injected with untreated cells and (b) nude mice injected with IL-6-treated cells. [21][22][23] also cannot account for the differentiation block because M1Myc/Egr-1 cells terminally differentiated in the absence of p21 expression. 24 Other target genes of Egr-1 that are potential regulators of hematopoietic development include TGF-b and p35.…”

Section: Discussionmentioning

confidence: 99%

Leukemia suppressor function of Egr-1 is dependent on transforming oncogene

2008

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We have shown that deregulated expression of either c-Myb or E2F-1 blocks terminal differentiation of M1 myeloid leukemia cells at the blast stage, whereas deregulated c-Myc blocks differentiation at the intermediate stage. Each of these oncogenes potentiates M1 leukemia in vivo. The zinc-finger transcription factor Egr-1 abrogates the block in M1 terminal differentiation imparted by oncogenic c-Myc or E2F-1, suppressing their leukemia-promoting function in nude mice. In this study, we asked whether Egr-1 also abrogates the block in terminal differentiation and suppresses leukemia imparted by deregulated c-Myb. Interestingly, the ectopic expression of Egr-1 in M1 cells expressing deregulated c-Myb only partially abrogated the block in terminal differentiation and did not suppress the leukemic phenotype. Two important implications from these data are that the leukemia suppressor function of Egr-1 is not directly related to how early the transforming oncogene blocks the differentiation program and that the tumor suppressor function of Egr-1 is dependent on the specific oncogene. Egr-1 is dominant to c-Myc-and E2F-1-, but not to c-Myb-, driven leukemia. These findings extend the notion that the molecular nature of genetic lesions responsible for leukemia determines the effectiveness of any given tumor suppressor.

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Section: Discussionmentioning

confidence: 99%

Leukemia suppressor function of Egr-1 is dependent on transforming oncogene

2008

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“…As a result of PML/RARa binding, transcription of these genes is likely to be repressed, but may also become RA-activated. In that sense, transglutaminase, LAP and p21 were shown to be preferential PML/RARa target genes (Casini and Pelicci, 1999;Gianni' et al, 1995). Second, on canonical RAREs, there is a dynamic balance between PML/RARa and RARa binding.…”

Section: What Are the Functional Consequences Of Pml/rara Degradationmentioning

confidence: 99%

Pathways of retinoic acid- or arsenic trioxide-induced PML/RARα catabolism, role of oncogene degradation in disease remission

Zhu

Lallemand-Breitenbach

2001

Oncogene

148

130

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Although there is evidence to suggest that PML/RARa expression is not the sole genetic event required for the development of acute promyelocytic leukemia (APL), there is little doubt that the fusion protein plays a central role in the initiation of leukemogenesis. The two therapeutic agents, retinoic acid and arsenic, that induce clinical remissions in APL, both target the oncogenic fusion protein, representing the ®rst example of oncogene-directed cancer therapy. This review focuses on the molecular mechanisms accounting for PML/RARa degradation. Each drug targets a speci®c moiety of the fusion protein (RARa for retinoic acid, PML for arsenic) to the proteasome. Moreover, both activate a common caspase-dependent cleavage in the PML part of the fusion protein. Speci®c molecular determinants (the AF2 transactivator domain of RARa for retinoic acid and the K160 SUMO-binding site in PML for arsenic) are respectively implicated in RA-or arsenic-triggered catabolism. The respective roles of PML/RARa activation versus its catabolism are discussed with respect to di erentiation or apoptosis induction in the context of single or dual therapies. Oncogene (2001) 20, 7257 ± 7265.

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“…To directly address its role in retinoid-signaling, we used cells from mice with targeted disruption of 4e-bp1 gene. Our data demonstrate that ATRAdependent upregulation of p21 Waf1/Cip1 , a protein that plays a key role in growth-inhibitory and pro-apoptotic responses (9)(10)(11)(12), is enhanced in 4e-bp1 knockout-cells. Similarly, siRNAmediated knockdown of 4E-BP1 in APL-derived cells results in p21 Waf1/Cip1 -upregulation.…”

Section: Introductionmentioning

confidence: 65%

“…We examined the ATRA-dependent induction of expression of p21 Waf1/Cip1 protein, a CDK inhibitor (19) that plays key role in the antiproliferative effects of ATRA (9)(10)(11)(12)(20)(21)(22). ATRA-treatment of 4E-BP1+/+ MEFs resulted in induction of p21 protein-expression, seen after 24−48 hours of treatment ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Role of the translational repressor 4E-BP1 in the regulation of p21Waf1/Cip1 expression by retinoids

Kannan-Thulasiraman

Dolniak²,

Kaur³

et al. 2008

Biochemical and Biophysical Research Communications

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The mechanisms by which retinoids regulate initiation of mRNA translation for proteins that mediate their biological effects are not known. We have previously shown that all-trans-retinoic acid (ATRA) induces mTOR-mediated activation of the p70 S6 kinase, suggesting the existence of a mechanism by which retinoids may regulate mRNA translation. We now demonstrate that treatment of acute promyelocytic leukemia (APL)-derived NB4 cells with ATRA results in dissociation of the translational repressor 4E-BP1 from the eukaryotic initiation factor eIF4E, and subsequent formation of eIF4G-eIF4E complexes. We also show that siRNA-mediated inhibition of 4E-BP1 expression enhances ATRA-dependent upregulation of p21 Waf1/Cip1 , a protein that plays a key role in the induction of retinoid-dependent responses. Our data also establish that ATRA-or cis-RA-dependent p21 Waf1/Cip1 protein expression is enhanced in mouse embryonic fibroblasts with targeted disruption of the 4e-bp1 gene, in the absence of any effects on the transcriptional regulation of the p21 Waf1/Cip1 gene. Moreover, generation of ATRA-or cis-retinoic acid (cis-RA)-antiproliferative responses is enhanced in 4E-BP1 knockout cells. Altogether, these findings strongly suggest a key regulatory role for the translational repressor 4E-BP1 in the generation of retinoid-dependent functional responses.

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A function of p21 during promyelocytic leukemia cell differentiation independent of CDK inhibition and cell cycle arrest

Cited by 86 publications

References 42 publications

Leukemia suppressor function of Egr-1 is dependent on transforming oncogene

Leukemia suppressor function of Egr-1 is dependent on transforming oncogene

Pathways of retinoic acid- or arsenic trioxide-induced PML/RARα catabolism, role of oncogene degradation in disease remission

Role of the translational repressor 4E-BP1 in the regulation of p21Waf1/Cip1 expression by retinoids

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