# REGULATION OF PROLYL HYDROXYLASE

> **NIH NIH R01** · UNIV OF MED/DENT NJ-R W JOHNSON MED SCH · 1992 · $203,631

## Abstract

The regulation of collagen has clear health-related implications because a
number of human diseases or dysfunctions such as rheumatoid arthritis,
pulmonary fibrosis, cirrhosis, atherosclerosis, acute and chronic
inflammation, Ehler's Danlos syndromes, Osteogenesis Imperfecta and wound
healing are associated with a change in collagen metabolism.  The overall
objective of this study is to understand how collagen production is
regulated in fibroblasts and how its regulation is coordinated with
regulation of prolyl hydroxylase and protein disulfide isomerase, enzymes
that catalyze essential posttranslational modifications of collagen.
Although low levels of several posttranslational modifying enzymes cause
nonlethal connective tissue disorders, the synthesis of hydroxyproline is
essential for collagen production and fiber formation.  The rate of
collagen production, the activity of prolyl hydroxylase and the activity of
protein disulfide isomerase are intimately related.  For example, if prolyl
hydroxylase activity is low, underhydroxylated collagen is produced which
is subject to enhanced intracellular degradation.

Prolyl hydroxylase is a tetrameric glycoprotein, alpha2beta2, where alpha
and beta are nonidentical polypeptides of molecular weights 64 kd and 60
kd.  We have recently cloned and sequenced a cDNA for most of the alpha
subunit of chick prolyl hydroxylase.  From our data on the cDNA and from
amino acid sequencing we have determined the primary structure for the
chick alpha subunit.  It has been shown that the beta subunit of prolyl
hydroxylase is identical to protein disulfide isomerase (PDI), thyroid
hormone binding protein, P55, and glycosylation site binding protein
(GSSP).  This unusual protein is the major resident protein of the
endoplasmic reticulum.  Half of the prolyl hydroxylase in cultured
fibroblasts contains tetrameres containing alpha' subunits which differ
from alpha in having two high mannose oligosaccharides per polypeptide
instead of one as in alpha.  When prolyl hydroxylase is synthesized only
new alpha and alpha' are translated; beta is derived from a per-existing
pool of beta-like cross-reacting protein (CRP) that is identical to protein
disulfide isomerase.

Elucidating the structure and regulation of the alpha subunit will provide
the basis for the design of antifibrotic drugs.  An understanding of the
expression and regulation of prolyl hydroxylase will no doubt advance the
development of therapy for fibrotic diseases such as scleroderma for which,
despite decades of work, there exists no effective therapy today.

The aims of the present proposal are:  (1) to isolate and sequence the gene
for the alpha/alpha' subunit of chick prolyl hydroxylase; (2) to measure
mRNA levels for alpha and beta subunits and compare these levels with the
levels of mRNA for the type I collagen alpha1 and alpha2 chains to see if
these polypeptides are coordinately regulated; (3) to measure the
transcription rates of alpha and beta; (4) to...

## Key facts

- **NIH application ID:** 3156117
- **Project number:** 5R01AR031839-07
- **Recipient organization:** UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
- **Principal Investigator:** RICHARD A BERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $203,631
- **Award type:** 5
- **Project period:** 1983-04-01 → 1995-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3156117

## Citation

> US National Institutes of Health, RePORTER application 3156117, REGULATION OF PROLYL HYDROXYLASE (5R01AR031839-07). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3156117. Licensed CC0.

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