Transactivation through Ets and Ap1 transcription sites determines the expression of the tumor-suppressing gene maspin.
Tumor invasion and metastasis are processes poorly understood at the molecular level. Maspin is a serine protease inhibitor (serpin) with tumor-suppressing function in the mammary gland. Maspin gene expression is decreased with malignancy and is lost in metastatic cells. We show in this report that differential expression of maspin in normal and carcinoma-derived mammary epithelial cells is regulated at the transcriptional level. We have identified the Ets and Ap1 sites in the maspin promoter that are active in regulating maspin expression in normal mammary epithelial cells but inactive in tumor cells. The Ets site alone is sufficient to activate transcription in a heterologous promoter, whereas the Ap1 site cooperates with Ets in activation. The enhancing function by Ets and Ap1 elements is decreased in primary tumor cells (21NT) and is abolished in invasive tumor cells (MDA-231). Thus, loss of maspin expression during tumor progression results at least in part from the absence of transactivation through the Ets and Ap1 sites.
Zhang
M
M
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Maass
N
N
Magit
D
D
Sager
R
R
D033961:Adaptor Protein Complex 1; D033965:Adaptor Protein Complex alpha Subunits; D033942:Adaptor Proteins, Vesicular Transport; D001483:Base Sequence; D015152:Blotting, Northern; D001943:Breast Neoplasms; D002277:Carcinoma; D002460:Cell Line; D003001:Cloning, Molecular; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D033961:Adaptor Protein Complex 1; D033965:Adaptor Protein Complex alpha Subunits; D033942:Adaptor Proteins, Vesicular Transport; D008565:Membrane Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; C085344:SERPIN-B5; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D014157:Transcription Factors