Posttranscriptional stabilization underlies p53-independent induction of p21WAF1/CIP1/SDI1 in differentiating human leukemic cells.

Schwaller, J; Koeffler, H. Phillip; Niklaus, Gisela; Loetscher, Pius; Nagel, Stefan; Fey, MF; Tobler, Andreas

doi:10.1172/jci117806

Cited by 115 publications

(77 citation statements)

References 38 publications

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“…Our data suggests the presence of both transcriptional and posttranscriptional components in the Ras-regulation of p21 that may be determined by the level of Ras expression. p53 is a potent transcriptional activator of p21 expression, but also p53 independent events including stimulation with growth factors or tumor promoters (Datto et al, 1995a;Michieli et al, 1994;Schwaller et al, 1995;Zeng and El-Deiry, 1996), expression of tumor suppressors (Englert et al, 1997;Somasundaram et al, 1997) or Raf (Woods et al, 1997) regulate p21. As shown in Figure 1a, upon Ras-expression p53 is not upregulated.…”

Section: Discussionmentioning

confidence: 99%

“…p21 mRNA is not signi®cantly induced by conditional Ras expression As p21 is regulated both transcriptionally and posttranscriptionally (Liu et al, 1996c;Macleod et al, 1995;Schwaller et al, 1995;Zeng and El-Deiry, 1996), we were interested to analyse the level of p21-regulation by Ras. Northern blotting experiments revealed a slight increase in basal expression of p21 mRNA in the Ras-clones as compared to NIH3T3 cells and neo-clones (mean induction of 1.6-fold in Figure 5a).…”

Section: Mapk Kinase Inhibitor Pd 098059 Abolishes P21 Inductionmentioning

confidence: 99%

“…Furthermore, growth factors PDGF, FGF, and EGF (Michieli et al, 1994), as well as tumor suppressor gene WT1 (Englert et al, 1997) induce p21 mRNA levels. Besides transcriptional activation, phorbol ester and vitamin D 3 are demonstrated to induce p21 posttranscriptionally (Russo et al, 1995;Schwaller et al, 1995). Other posttranscriptional activators of p21 include okadaic acid (Zeng and El-Deiry, 1996), and diethylmaleate, which acts through the MAPK pathway (Russo et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Ras induces p21Cip1/Waf1 cyclin kinase inhibitor transcriptionally through Sp1-binding sites

et al. 1999

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p21 Cip1/Waf1 cyclin-dependent kinase inhibitor (p21) is inducible by Raf and mitogen-activated protein kinase kinase (MAPKK), but the level of regulation is unknown. We show here by conditional and transient Rasexpression models that Ras induces p21. Induction of p21 in conditionally Ras-expressing cells is posttranscriptional utilizing mitogen-activated protein kinase (MAPK) pathway. Transient, high-level Ras-expression induces transcriptional activation of p21 mediated by a GC-rich region in p21 promoter -83-54 bp relative to the transcription initiation site containing binding sites for Sp1-family transcription factors. Mutation of either Sp1-binding site 2 or 4 in this region decreases the magnitude of induction of promoter activity by Ras, but only the simultaneous mutation of both sites abolishes fully the induction. Electrophoretic mobility shift assays using an oligonucleotide corresponding to Sp1-binding site 2 indicate that both Sp1 and Sp3 transcription factors bind to this region. The results demonstrate that the central cytosolic growth regulator Ras is a potent transcriptional and posttranscriptional inducer of the nuclear growth inhibitor p21.

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Section: Discussionmentioning

confidence: 99%

Section: Mapk Kinase Inhibitor Pd 098059 Abolishes P21 Inductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ras induces p21Cip1/Waf1 cyclin kinase inhibitor transcriptionally through Sp1-binding sites

et al. 1999

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“…It is conceivable that the formation of cyclin/CDK/PCNA/p21cip1 complexes (Sherr and Roberts, 1995) may have contributed to the stabilization and accumulation of high levels of p21cip1 protein in the di erentiated keratinocytes that express HPV E7. Post-transcriptional regulation of p21cip1 and of p27kip1, a related CDK inhibitor, has also been demonstrated in cell lines of other lineages (Nourse et al, 1994;Macleod et al, 1995;Schwaller et al, 1995;Zeng and El-Deiry, 1996;Hengst and Reed, 1996;Timchenko et al, 1996). It is interesting to note that the cyclin/CDK/PCNA/ p21cip1 complexes are disrupted and the p21cip1 mRNA and protein become undetectable in cell lines that constitutively express the high-risk HPV E6 and E7 genes.…”

Section: Induction Of P21cip1 Protein In DI Erentiated Keratinocyte Rmentioning

confidence: 94%

Post-transcriptional induction of p21cip1 protein by human papillomavirus E7 inhibits unscheduled DNA synthesis reactivated in differentiated keratinocytes

et al. 1998

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Productive infection by human papillomaviruses (HPVs) occurs only in di erentiated squamous epithelial cells in papillomas, condylomata, and low grade intraepithelial neoplasias. Host DNA replication is reactivated in a fraction of terminally di erentiated keratinocytes in benign human lesions and in organotypic raft cultures of primary human keratinocytes (PHKs) transduced with retroviruses expressing HPV-18 E7 oncogene from its native upstream regulatory region (URR). Thus the natural function of E7 protein, which inactivates pRB family proteins, is to induce host genes essential to support viral DNA replication in post-mitotic cells. Using this raft culture model system, we show that HPV-18 URR-E7 induces the universal cyclin-dependent kinase inhibitor p21cip1 protein in a fraction of di erentiated PHKs. Induction is mediated by posttranscriptional mechanisms independent of p53. Double immuno¯uorescence studies demonstrate that, in raft cultures and in laryngeal papillomas, p21cip1 induction and reactivated host DNA synthesis take place in a mutually exclusive manner in PCNA-positive, di erentiated keratinocytes. We suggest that p21cip1 induction e ectively blocks unscheduled DNA synthesis reactivated by E7. These results begin to explain the inverse relationship between p21cip1 induction and HPV activities previously observed in a spectrum of benign lesions regardless of HPV types present.

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“…Increased expression of p21 is seen in di erentiating tissues in vivo (Parker et al, 1995). Its expression is also increased during the in vitro di erentiation of myocyte, hematopoietic, hepatoma, and neuroblastoma cells, induced by various types of agents including phorbol ester, vitamin D3, TNF-a, MyoD and nerve growth factor plus aphidicolin (Jiang et al, 1994;Steinman et al, 1994;Guo et al, 1995;Schwaller et al, 1995;Poluha et al, 1996;Yoshida et al, 1996). The level of p21 increases in di erentiating Caco2 and HT29 colon carcinoma cell lines (Gartel et al, 1996;Evers et al, 1996;Siavoshian et al, 1997;Goldberg et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Comparative effects of overexpression of p27Kip1 and p21Cip1/Waf1 on growth and differentiation in human colon carcinoma cells

et al. 1999

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Recent studies have shown that decreased expression of p27 Kip1 is associated with high grade tumors and an unfavorable prognosis in several types of human cancer. To clarify the role of p27 Kip1 in colon cancer, we have overexpressed this protein in the HT29 colon cancer cell line. The derivatives displayed an increase in the p27 Kip1 protein in cyclin E/CDK2 immunoprecipitates and a decrease in cyclin E-associated kinase activity when compared to vector control clones, providing evidence that the overexpressed protein was functional. Clones with a high level of p27 Kip1 displayed partial growth inhibition in monolayer culture and a decrease in plating e ciency, even though they expressed increased levels of the cyclin D1 protein. Using alkaline phosphatase expression as a marker, we found that the p27 Kip1 overexpressor clones displayed a 2 ± 3-fold increase in sensitivity to induction of di erentiation by 2 mM sodium butyrate. In contrast to these results, derivatives of HT29 cells that stably overexpressed p21 Cip1/Waf1 displayed decreased sensitivity to the induction of di erentiation. These ®ndings may explain why decreased levels of p27 Kip1 in certain human cancers is associated with high grade (poorly di erentiated) tumors, and suggest that strategies that increase the level of p27 Kip1 may be useful in cancer therapy.

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Posttranscriptional stabilization underlies p53-independent induction of p21WAF1/CIP1/SDI1 in differentiating human leukemic cells.

Cited by 115 publications

References 38 publications

Ras induces p21Cip1/Waf1 cyclin kinase inhibitor transcriptionally through Sp1-binding sites

Ras induces p21Cip1/Waf1 cyclin kinase inhibitor transcriptionally through Sp1-binding sites

Post-transcriptional induction of p21cip1 protein by human papillomavirus E7 inhibits unscheduled DNA synthesis reactivated in differentiated keratinocytes

Comparative effects of overexpression of p27Kip1 and p21Cip1/Waf1 on growth and differentiation in human colon carcinoma cells

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