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

Kivinen, Laura; Tsubari, Minna; Haapajärvi, Tarja; Datto, Michael B.; Wang, Xiao Fan; Laiho, Marikki

doi:10.1038/sj.onc.1203000

Cited by 60 publications

(72 citation statements)

References 56 publications

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“…Firstly, Sp1 activity is increased following phosphorylation by oncogenic signalling pathways such as the RAS/RAF/MAPK and the PI3K/Akt pathways (Kivinen et al, 1999;Milanini-Mongiat et al, 2002;Pore et al, 2004). Secondly, Sp1 is overexpressed and/or hyperactivated in a number of human tumours (Lietard et al, 1997;Zannetti et al, 2000;Shi et al, 2001;Chiefari et al, 2002;Wang et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Sp1 transcription factor induces apoptosis

et al. 2006

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Transcription factor Sp1 has recently been shown to be overexpressed in a number of human cancers and its overexpression contributes to malignant transformation. Sp1 regulates the expression of a number of genes participating in multiple aspects of tumorigenesis such as angiogenesis, cell growth and apoptosis resistance. To better understand the role of increased Sp1 levels on apoptosis regulation we have used retroviruses to overexpress this protein in haematopoietic Baf-3 cells and in 3T3 fibroblasts. We have also used inducible expression systems to control ectopic Sp1 levels in different cell types. Surprisingly, Sp1 overexpression on its own induces apoptosis in all the cellular models tested. The apoptotic pathways induced by Sp1 overexpression are cell type specific. Finally, using a truncated form of Sp1, we show that Sp1-induced apoptosis requires its DNA-binding domain. Our results highlight that Sp1 levels in untransformed cells must be tightly regulated as Sp1 overexpression leads to the induction of apoptosis. Our results also suggest that cancer cells overexpressing Sp1 can avoid Sp1-induced apoptosis.

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Section: Discussionmentioning

confidence: 99%

Overexpression of Sp1 transcription factor induces apoptosis

et al. 2006

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“…To date, two contradictory viewpoints can be found in the literature for depicting the relationship between Sp1 and p300. Studies based on p21 waf1 transcription suggested that the interaction between Sp1 and p300 was indirect (Owen et al, 1998;Kivinen et al, 1999;Xiao et al, 2000). On the contrary, other workers described a direct physical interaction between the acetyltransferase region of p300 and Sp1 DNA-binding domain (Suzuki et al, 2000).…”

Section: Ac-sp1mentioning

confidence: 99%

“…The presence of HAT activity endows p300/CBP with the capacity to influence chromatin activity by modifying nucleosomal histones (Chan and La Thangue, 2001). Existing data implicate that Sp1 and p300 may work in cooperation in transcriptional regulation of certain genes (Kivinen et al, 1999). Nevertheless, whether p300 participates in p16 transcriptional regulation has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

p300 plays a role in p16INK4a expression and cell cycle arrest

et al. 2007

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As a cyclin-dependent kinase inhibitor, p16 INK4a plays a key role in cell cycle progression and cellular differentiation, and its expression is frequently altered in human cancers through epigenetically mediated transcriptional silencing. In this report, we demonstrate that p300 was able to induce cell cycle arrest, and this process was reversed by p16 INK4a silencing by RNA interference in HeLa cells. We also show that p300 was involved in activation of p16 INK4a expression in 293T cells. Specifically, p300 cooperated with Sp1 to stimulate both p16 INK4a promoter activity and mRNA expression. Co-immunoprecipitation and mammalian twohybrid assays revealed that p300 and Sp1 formed a complex through interaction between the Q domain of p300 and the N-terminal domain of Sp1. The chromatin immunoprecipitation assays verified that p300 was recruited to p16 INK4a promoter, and the histone acetyltransferase domain of p300 participated in p16 INK4a activation through inducing hyperacetylation of histone H4 at p16 INK4a gene. These data suggest that p300 plays a critical role in transcriptional regulation of p16 INK4a and in cell cycle arrest.

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“…3, Ras signalling can inactivate p21 through cyclin D1-mediated sequestration. In addition, Ras can stabilize the p21 protein 131 and induce p21 expression through multiple mechanisms 82,132 .…”

Section: Linking Opposing Forces In Cancermentioning

confidence: 99%

KLF4, p21 and context-dependent opposing forces in cancer

2005

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| Krüppel-like factors are transcriptional regulators that influence several cellular functions, including proliferation. Recent studies have shown that one family member, KLF4, can function both as a tumour suppressor and an oncogene. The ability of KLF4 to affect the levels of expression of the cell-cycle regulator p21 seems to be involved, in that this protein might function as a switch that determines the outcome of KLF4 signalling. Is this role of p21 restricted to KLF4, or does p21 represent a nodal point for signals from multiple other factors with opposing functions in cancer?

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

Cited by 60 publications

References 56 publications

Overexpression of Sp1 transcription factor induces apoptosis

Overexpression of Sp1 transcription factor induces apoptosis

p300 plays a role in p16INK4a expression and cell cycle arrest

KLF4, p21 and context-dependent opposing forces in cancer

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