HETEROGENEITY OF HUMAN COLON CARCINOMA

  • Brattain, Michael G, (PI)

Project: Research project

Description

DESCRIPTION: During the previous years of this project, the applicant has found that TGF-alpha transfection of early malignant colon carcinoma cells results in the acquisition of growth factor independence (GFI) with increased tumorigenicity in athymic nude mice. Similarly, anti-sense TGF-alpha expression in late malignant colon cancer cells decreases tumorigenicity and induces the re-acquisition of growth factor dependence (GFD). GFI appears to be related to aberrant expression of TGF-alpha in non-dividing growth states where it is normally downregulated. This aberrant TGF-alpha expression in late malignant cells depends upon dysregulation of transcriptional control. The cis-element of the TGF-alpha promotor mediating dysregulation has been identified and characterized. In addition, the applicant has demonstrated that aberrant expression of TGF-alpha allowed for continued EGF receptor (EGFR) activation in non-dividing states. Thus, the applicant now wants to characterize the transcription factors necessary for autostimulatory regulation of the TGF-alpha promotor dysregulative cells. Gel shift analyses suggest that downregulation of trans-acting factors that bind with the cis-element for TGF-alpha autoregulation occurs in quiescent GFD cells, while GFI cells show constitutive expression of these factors in growth arrested states. In GFD cells, insulin-like growth factor I (IGF-I) stimulates EGFR and entry into S phase. Therefore, the applicant proposes to study how IGF-I-R acts as a cofactor for entry into DNA synthesis. Thus, the specific aims of this application are, first, to characterize the TGF-alpha autoregulatory transcription factors. The second specific aim is to determine the mechanistic basis for the downregulation of TGF-alpha autocrine activity in GFD cells and its dysregulation in GFI cells. The final specific aim is to determine the effects of autocrine TGF-alpha dysregulation on the control of cell cycle transit.
StatusFinished
Effective start/end date2/1/8211/30/14

Funding

  • National Institutes of Health: $246,886.00
  • National Institutes of Health: $118,886.00
  • National Institutes of Health: $338,323.00
  • National Institutes of Health: $315,897.00
  • National Institutes of Health
  • National Institutes of Health: $267,583.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $306,420.00
  • National Institutes of Health: $252,549.00
  • National Institutes of Health: $306,420.00
  • National Institutes of Health: $11,802.00
  • National Institutes of Health: $219,088.00
  • National Institutes of Health
  • National Institutes of Health: $350,083.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $338,920.00
  • National Institutes of Health: $335,424.00
  • National Institutes of Health: $315,897.00
  • National Institutes of Health: $201,519.00
  • National Institutes of Health: $39,715.00
  • National Institutes of Health: $288,034.00
  • National Institutes of Health: $346,046.00
  • National Institutes of Health: $167,585.00
  • National Institutes of Health

Fingerprint

Colon
Carcinoma
Transforming Growth Factor alpha
Intercellular Signaling Peptides and Proteins
Colonic Neoplasms
Cell Survival
Phosphatidylinositol 3-Kinases
Phosphotransferases
Mutation
Neoplasm Metastasis
Phospholipase C gamma
Cell Line
Down-Regulation
Dimethylformamide
Survival
Growth
Transforming Growth Factors
Phenotype
Tretinoin
Molecular Weight

ASJC

  • Medicine(all)