Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3 Journal Article


Authors: Leslie, K.; Lang, C.; Devgan, G.; Azare, J.; Berishaj, M.; Gerald, W.; Kim, Y. B.; Paz, K.; Darnell, J. E.; Albanese, C.; Sakamaki, T.; Pestell, R.; Bromberg, J.
Article Title: Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3
Abstract: Signal transducers and activators of transcription 3 (STAT3) is a transcription factor that is aberrantly activated in many cancer cells. Constitutively activated STAT3 is oncogenic, presumably as a consequence of the genes that it differentially regulates. Activated STAT3 correlated with elevated cyclin D1 protein in primary breast tumors and breast cancer-derived cell lines. Cyclin D1 mRNA levels were increased in primary rat-, mouse-, and human-derived cell lines expressing either the oncogenic variant of STAT3 (STAT3-C) or vSrc, which constitutively phosphorylates STAT3. Mutagenesis of STAT3 binding sites within the cyclin D1 promoter and chromatin immunoprecipitation studies showed an association between STAT3 and the transcriptional regulation of the human cyclin D1 gene. Introduction of STAT3-C and vSrc into immortalized cyclin D1-/- and cyclin D1-/+ fibroblasts led to anchorage-independent growth of only cyclin D1-/+ cells. Furthermore, knockdown of cyclin D1 in breast carcinoma cells led to a reduction in anchorage-independent growth. Phosphorylation of the retinoblastoma (Rb) protein [a target of the cyclin D1/cyclin-dependent kinase 4/6 (cdk4/6) holoenzyme] was delayed in the cyclin D1-/- cells relative to cyclin D1-/+ cells. The E7 oncogene, whose activity includes degradation of Rb and dissociation of Rb from E2F, did not confer anchorage-independent growth to the cyclin D1-/- cells but, in conjunction with vSrc, resulted in robust growth in soft agar. These results suggest both a cdk-dependent and cdk-independent role for cyclin D1 in modulating transformation by different oncogenes. ©2006 American Association for Cancer Research.
Keywords: immunohistochemistry; controlled study; protein phosphorylation; human cell; nonhuman; protein analysis; animal cell; mouse; animals; mice; stat3 protein; small interfering rna; rna, small interfering; cell line, tumor; breast neoplasms; cell transformation, neoplastic; oncogene; dna; transcription regulation; genetic transfection; messenger rna; rna, messenger; chromatin immunoprecipitation; breast tumor; cell growth processes; western blotting; plasmid; stat3 transcription factor; mutagenesis, site-directed; binding sites; rats; cyclin d1; luciferases; tubulin; gel mobility shift assay; cell adhesion; anchorage independent growth; g1 phase; nih 3t3 cells; enzyme assay; northern blotting; rna analysis; papillomavirus e7 proteins; promoter regions (genetics); trans-activation (genetics)
Journal Title: Cancer Research
Volume: 66
Issue: 5
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2006-03-01
Start Page: 2544
End Page: 2552
Language: English
DOI: 10.1158/0008-5472.can-05-2203
PUBMED: 16510571
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 80" - "Export Date: 4 June 2012" - "CODEN: CNREA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Janeen R Azare
    7 Azare
  2. Jacqueline Bromberg
    104 Bromberg
  3. Geeta Devgan
    4 Devgan
  4. William L Gerald
    370 Gerald
  5. Kenneth Andrew Leslie
    8 Leslie
  6. Cynthia Lang
    1 Lang