# GLUCOCORTICOID INHIBITION OF PLASMINOGEN ACTIVATOR

> **NIH NIH R01** · YALE UNIVERSITY · 1988 · $134,064

## Abstract

Plasminogen activators (PAs) are specialized proteases which are highly
specific for the inactive zymogen plasminogen, which, upon cleavage by PAs,
forms the active serine protease plasmin.  PAs, which are expressed by both
normal and malignant cell types, are frequently regulated by steroid and
peptide hormones.  It has been suggested that PA expression may be related
to regulation of cell growth and/or differentiation state.  We have
demonstrated that LICR-LON-HMy2 human myeloma lymphoblast cells (HMy2
cells) secrete the PA urokinase (UK).  These cells are growth inhibited by
glucocorticoids, and their extracellular UK activity is virtually
eliminated following exposure to glucocorticoids.  This inhibition of UK is
unrelated to glucocorticoid induction of inhibitors to either UK or
activated plasmin.  We propose to examine the mechanisms of glucocorticoid
inhibition of HMy2 UK.  We will establish 1) whether inhibition of
extracellular UK involves decreased biosynthesis and/or secretion of UK; 2)
whether decreases in steady-state levels of mRNA coding for UK are
involved; 3) whether decreased transcription of the UK gene occurs; and 4)
whether decreased UK gene transcription is a primary effect of
glucocorticoids or whether it is mediated by glucocorticoid-induced
transcriptional factors.  The molecular biology approaches will be
facilitated by the use of the human UK cDNA plasmid pHUK-8, which has been
supplied to us by Dr. F. Blasi (currently at NIH).  Appropriate contingency
plans for all possible outcomes are discussed.  The experiments outlined in
this proposal will establish the validity of using glucocorticoid
inhibition of HMy2 UK in future studies to examine mechanisms by which
steroid-receptors turn off constitutive gene transcription.  Such future
studies would contrast with the many systems currently being used to
examine steroid induction of specific genes.  In summary, this work will
provide the groundwork for a number of significant long-range goals:  1)
examining the mechanisms of glucocorticoid inhibition of constitutive gene
transcription; 2) studying potential relationships between glucocorticoid
inhibition of UK, inhibition of cell growth, and development of steroid
resistance in myeloma lymphoblasts; and 3) development of a potentially
important clinical assay for prediction of glucocorticoid responsiveness in
myeloma patients.

## Key facts

- **NIH application ID:** 3179450
- **Project number:** 5R01CA040010-03
- **Recipient organization:** YALE UNIVERSITY
- **SAM.gov UEI:** FL6GV84CKN57
- **Principal Investigator:** BRUCE A LITTLEFIELD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1988
- **Award amount:** $134,064
- **Award type:** 5
- **Project period:** 1986-04-01 → 1989-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3179450

## Citation

> US National Institutes of Health, RePORTER application 3179450, GLUCOCORTICOID INHIBITION OF PLASMINOGEN ACTIVATOR (5R01CA040010-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3179450. Licensed CC0.

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