Skip to main content

Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.

Publication ,  Journal Article
De Siervi, A; Marinissen, M; Diggs, J; Wang, X-F; Pages, G; Senderowicz, A
Published in: Cancer Res
January 15, 2004

Alkylphospholipids (ALKs) are a novel class of antitumor agents with an unknown mechanism of action. The first ALK tested in the clinic, miltefosine, has been approved recently in Europe for the local treatment of patients with cutaneous metastasis. Perifosine, the only available oral ALK, is being studied currently in human cancer clinical trials. We have shown previously that perifosine induces p21(waf1/cip1) in a p53-independent fashion and that induction of p21(waf1/cip1) is required for the perifosine-induced cell cycle arrest because cell lines lacking p21(waf1/cip1) are refractory to perifosine. In this report, we investigated the mechanism by which perifosine induces p21(waf1/cip1) protein expression. We observed that perifosine induces the accumulation of p21(waf1/cip1) mRNA without affecting p21(waf1/cip1) mRNA stability. Using several p21(waf1/cip1) promoter-driven luciferase reporter plasmids, we observed that perifosine activates the 2.4-kb full-length p21(waf1/cip1) promoter as well as a p21 promoter construct lacking p53-binding sites, suggesting that perifosine activates the p21(waf1/cip1) promoter independent of p53. The minimal p21 promoter region required for perifosine-induced p21 promoter activation contains four consensus Sp1-binding sites. Mutations in each particular Sp1 site block perifosine-induced p21(waf1/cip1) expression. Moreover, we showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of Sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased Sp1 binding and enhanced p21(waf1/cip1) transcription. These results represent a novel mechanism by which alkylphospholipids modulate transcription, and may contribute to the discovery of new signal transduction pathways crucial for normal and neoplastic cell cycle control.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

January 15, 2004

Volume

64

Issue

2

Start / End Page

743 / 750

Location

United States

Related Subject Headings

  • Transcriptional Activation
  • Sp1 Transcription Factor
  • Promoter Regions, Genetic
  • Phosphorylcholine
  • Phospholipids
  • Oncology & Carcinogenesis
  • Mutagenesis
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 1
 

Citation

APA
Chicago
ICMJE
MLA
NLM
De Siervi, A., Marinissen, M., Diggs, J., Wang, X.-F., Pages, G., & Senderowicz, A. (2004). Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1. Cancer Res, 64(2), 743–750. https://doi.org/10.1158/0008-5472.can-03-2505
De Siervi, Adriana, Maria Marinissen, Jessica Diggs, Xiao-Fan Wang, Gilles Pages, and Adrian Senderowicz. “Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.Cancer Res 64, no. 2 (January 15, 2004): 743–50. https://doi.org/10.1158/0008-5472.can-03-2505.
De Siervi, Adriana, et al. “Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.Cancer Res, vol. 64, no. 2, Jan. 2004, pp. 743–50. Pubmed, doi:10.1158/0008-5472.can-03-2505.

Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

January 15, 2004

Volume

64

Issue

2

Start / End Page

743 / 750

Location

United States

Related Subject Headings

  • Transcriptional Activation
  • Sp1 Transcription Factor
  • Promoter Regions, Genetic
  • Phosphorylcholine
  • Phospholipids
  • Oncology & Carcinogenesis
  • Mutagenesis
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 1