CARCINOGEN SUPPRESSION OF KERATINOCYTE DIFFERENTIATION

  • Rice, Robert H, (PI)

Project: Research project

Description

This proposal explores physiological and molecular mechanisms by
which 3 model carcinogens suppress keratinocyte differentiation
in serially cultivated human squamous carcinoma cells. First, the
action of the potent animal carcinogen and tumor promoter
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in suppressing
accumulation of the particulate transglutaminase and the 56-58
kd keratins will be investigated. To test the hypothesis that this
suppression is mediated by vitamin A as a consequence of TCDD
antagonism of hydrocortisone action, the effect of TCDD on
expression of transglutaminase and kertains will be measured in
the absence of endogenous vitamin A. The influence of TCDD on
retinol uptake and metabolism, levels of the cellular retinol
binding and glucocorticoid receptor proteins and whether the
suppression of differentiated function occurs at the
transcriptional or translational level will then be studied. Second,
the uncoupling of involucrin and particulate transglutaminase
expression by benzo(a) pyrene will be investigated. This model
carcinogen may arrest the cellular differentiation in what is
ordinarily a transitory intermediate state. A limited survey of
polycyclic aromatic hydrocarbons and related compounds will be
undertaken to find whether this property is characteristic of
inducers of aryl hydrocarbon hydroxylase. In addition, possible
benzo(a)pyrene uncoupling of the differentiation program in
normal human epidermal cells and a continuous line of
premalignant human keratinocytes will be tested. Third, the
phorbol ester promoter-mediated suppression of transglutaminase
and involucrin will be investigated. This response will be
characterized kinetically, and the activity of several structurally
related and unrelated compounds examined. The role of
diacylglycerol in governing the response, including possible
generation of this activator of protein kinase C by physiological
effectors, will be explored. The results may help to elucidate
retinoid-glucocorticoid interactions influencing keratinocyte
physiology and to resolve factors coordinating keratinocyte
differentiation. Moreover, in furthering our physiological and
molecular understanding of target cell response to carcinogens,
this work may permit refinements in assessing human risk posed
by environmental agents.
StatusFinished
Effective start/end date3/1/882/28/92

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Keratinocytes
Carcinogens
Transglutaminases
Vitamin A
Aryl Hydrocarbon Hydroxylases
Aromatic Hydrocarbons
Benzo(a)pyrene
Glucocorticoid Receptors
Keratins
Protein Kinase C
Glucocorticoids
Hydrocortisone
Squamous Cell Carcinoma
Esters
Polychlorinated Dibenzodioxins
Neoplasms
Proteins
involucrin

Keywords

  • Medicine(all)