# THE CYTOLOGICAL AND PHYSIOLOGICAL MODE OF AP4A ACTION

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 1987 · $135,359

## Abstract

Diadenosine 5' ,5'''-P1,P4-tetraphosphate (Ap4A), a nucleotide formed
in the back reaction of the aminoacid activation step, is ubiquitously
present in bacterial and animal cells.  The enzyme-catalyzed synthesis of
Ap4A from ATP and certain aminoacyladenylates is enhanced by the presence
of Zn2+.  Several lines of evidence point to possible involvement of
Ap4A in aspects of cellular proliferation, DNA replication, heat shock
response and cell oxidation.  An Ap4A binding protein, which is
associated with the high molecular weight form of DNA polymerase alpha of
calf thymus and HeLa cell and which binds Ap4A noncovalently with high
affinity and great substrate specificity, has been isolated and
characterized.  Relatively high levels of Ap4A are present in blood
platelets and these Ap4A pools are quantitatively released when platelets
are induced to aggregate.  Our working hypothesis is that Ap4A may be a
signal for the induction of the heat shock or stress response in bacterial
and animal cells as well as a possible signal for the induction of the host
acute phase responses to a variety of infections, injury, and other
physical insults in live animals.  The physiological response of live
animals could be mediated by increases in plasma Ap4A levels produced by
platelets' aggregation, which is induced by the above-mentioned trauma.
The heat shock or acute phase response is manifested by induction of the
synthesis of groups of proteins (different proteins for each of these two
phenomena) which presumably enable the individual cells or the whole animal
to adapt to external conditions which affect cellular growth or survival.
The proposed project is designed to:  (1) elucidate the mechanism of
cellular Ap4A synthesis in bacterial and animal cells; (2) study the
mechanism of Ap4A interaction with the DNA replicative machinery in
mammalian cells; (3) establish the physiological response of animals (rats,
mice) to increase in serum Ap4A levels which may be produced by
thrombocytopenia; and, (4) identify the role of Ap4A in tumor metastasis
in light of the recently identified correlations between cellular Ap4A
metabolism and the metastatic propensity of cells, and the well-established
relationship between platelets' aggregation and tumor metastases in vivo.
The long term objectives of these studies are the understanding of Ap4A
action at the cellular and physiological levels.  The significance of the
proposed project is in establishing the mode and mechanism of action of a
potential intracellular mediator which signals the cellular response to
external conditions affecting growth or survival.  (G)

## Key facts

- **NIH application ID:** 3178124
- **Project number:** 5R01CA039294-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **SAM.gov UEI:** FBYMGMHW4X95
- **Principal Investigator:** ELIEZER RAPAPORT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $135,359
- **Award type:** 5
- **Project period:** 1985-04-01 → 1988-10-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3178124

## Citation

> US National Institutes of Health, RePORTER application 3178124, THE CYTOLOGICAL AND PHYSIOLOGICAL MODE OF AP4A ACTION (5R01CA039294-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3178124. Licensed CC0.

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