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Structural and functional comparison of the genes for human platelet factor
4 and PF4alt
R Eisman, S Surrey, B Ramachandran, E Schwartz and M Poncz
Division of Hematology, Children's Hospital of Philadelphia, PA 19104.
Platelet factor 4 (PF4) is a 70 amino acid heparin-binding protein released
from the alpha-granules of activated platelets. Its exact biologic function
is not known, although PF4 is a member of a multigene family involved in
chemotaxis, coagulation, inflammation, and cell growth. We previously
cloned the cDNA for human PF4 from a human erythroleukemic (HEL) cell
expression library. We now report the isolation and sequence determination
of the gene for human PF4. This gene contains three exons and spans
approximately 1,000 basepairs (bp). Concurrently, we have cloned a highly
homologous gene that we have called PF4alt. We show that PF4 and PF4alt are
non-allelic genes: the human PF4 gene is encoded on a 10 kilobasepairs (kb)
EcoRI fragment, and its DNA sequence agrees with protein and cDNA data for
PF4, while PF4alt is encoded in a polymorphic 3 or 5 kb EcoRI fragment.
Compared with PF4, this gene has 14% DNA and 38% amino acid divergence in
the signal peptide region, and 2.6% DNA and 4.3% amino acid divergence in
the coding region of the mature protein. PF4alt contains three amino acid
substitutions (P58----L, K66----E, and L67----H) near the C- terminus, in a
region known to be critical for PF4 function. Primer extension studies show
the 5'-untranslated region of PF4 is 73 bp long. A TATA box is present 30
bp 5' to the transcription start site. A 90 bp stretch of pyrimidines
(including 53 consecutive thymidine residues) begins at -227 bp and is
analogous to a similar region of 30 residues 5' to the rodent PF4 gene.
This pyrimidine-rich region is absent from the PF4alt gene; however, DNA
homology exists between the two human genes in the 5'- and 3'-flanking
regions and extends for over 3.6 kb. Alternating purine/pyrimidine tracts
occur both 5' and 3' to PF4 and PF4alt but do not define the endpoints of
the gene duplication, which extend beyond these sequences at least at the
5' end. Northern blot analysis using gene-specific oligonucleotides and
platelet RNA showed an 800 or 900 nucleotide (n) message for PF4 and
PF4alt, respectively. Northern blot and primer extension studies show that
steady-state platelet PF4 mRNA levels are approximately one magnitude
greater than PF4alt mRNA levels. Thus, these studies demonstrate that
PF4alt mRNA is expressed in platelets. Whether PF4alt protein is expressed
remains to be determined, and the nature of its biologic function needs to
be studied.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 76,
Issue 2,
pp. 336-344,
07/15/1990
Copyright © 1990 by The American Society of Hematology
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