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Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4390-4391
CORRESPONDENCE
A Response to AC133 Hematopoietic Stem Cell Antigen: Human
Homologue of Mouse Kidney Prominin or Distinct Member of a Novel
Protein Family?
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LETTER |
Three recently published works represent the first descriptions of a
potential new family of 5-trans-membrane cell surface glycoproteins.1,2,3 The human AC133 molecule2,3
may indeed be the homologue of mouse prominin,1,4 and Drs
Weigmann and colleagues have very carefully discussed the evidence for and against this relationship. We agree with the arguments put forward
by these authors, and that further work is clearly needed to examine
the possible localization of AC133 antigen to plasma membrane
protrusions, and to assess the expression of prominin on murine
hematopoietic stem cells.
If prominin proves to be a marker of primitive murine stem cells, as
AC133 is in humans, its value in studies of murine hematopoiesis would
be considerable. To assist these studies, we have also isolated and
characterized a prominin-like cDNA from mouse brain. This murine
sequence differs slightly from the prominin sequence, as we have
identified an additional block of nine amino acids within the
N-terminal domain. These nine amino acids are strongly homologous to
the corresponding human sequence (Fig 1).The cDNA isolated from mouse brain therefore predicts a protein of 867 amino acids, with a molecular weight of 97.3 kD.5 The
presence of murine AC133 transcript in a variety of mouse tissues was
assessed by Northern analysis (Fig 2). A 4.4-k mRNA
transcript was detectable in mouse embryo at 7 days, peaking at 11 days, and tapering off at days 15 and 17 while still being clearly
detectable. In adult mouse tissue, the transcript is weakly detectable
in brain, lung, skeletal muscle, and more intensely in kidney and
testis. Molecular analysis of the three proteins from
human, mouse and Caenorhabtidis elegans6 indicate that all three contain leucine zipper
consensus sequences (on the first extracellular loop in the human and
mouse, and on the second in C elegans). There are conserved
cysteine residues in all three molecules appearing at the beginning of
each small cytoplasmic loop. Although the mouse and human proteins
exhibit strong conservation in all five predicted transmembrane
sequences, the greatest degree of conservation with the C
elegans sequence is within TM3, where 7 out of 22 amino acids are
conserved in all three species. There are seven tyrosine residues
within the C-terminal cytoplasmic tail in C elegans;
however, none of them occur within a tyrosine phosphorylation consensus
sequence. The cytoplasmic tails of the mouse and human proteins contain
five tyrosine residues, the first of which is a tyrosine
phosphorylation consensus sequence that is completely identical in both
proteins. Another sequence7 in the Expressed Sequence
Tag database, derived from murine embryo, has
approximately 25% homology to the human and mouse AC133
antigen/prominin sequences, indicating that these two molecules may
indeed be the first described of a new family of cell surface
receptors.
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| Fig 1.
Alignment of human AC133, mouse AC133, and mouse prominin
sequences, showing the position of a presumed nine-amino acid deletion in the mouse prominin sequence.
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| Fig 2.
Northern analysis of murine AC133 antigen mRNA
expression. Multiple tissue poly A+ Northern blots were
purchased from Clontech (San Diego, CA) and probed with
32P murine AC133 antigen cDNA. (A) Expression of message is
detectable in mouse embryo peaking at day 11, and then tapering off to
still detectable levels at days 15 and 17. (B) In adult tissues,
message is detectable in brain, lung, skeletal muscle, kidney, and
testis.
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The expression of such a gene or gene family on hematopoeitic human
stem cells, mouse embryo, and adult tissues, and in a phylogenetically
less evolved organism such as C elegans may indicate an
important role for this five-transmembrane protein structure in
development and/or cell signaling. In particular,
the localization of the prominin molecule to cellular protrusions
places this molecule in an optimal locale to participate in cellular
communications via cell-cell contact, and possibly
signaling.
Sheri Miraglia
PE Applied
Biosystems
Foster City, CA
Wayne Godfrey
Department of
Hematology
Stanford University Medical Center
Stanford,
CA
David Buck
AmCell Corp
Sunnyvale, CA
| |
REFERENCES |
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Corbeil D,
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Huttner WB:
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AC133 hematopoietic stem cell antigen: Human homologue of mouse kidney prominin or distinct member of a novel protein family?
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