Usage And Synthesis
Human PTHrP encodes a signal peptide of 36 aa and a
141-aa mature protein. In teleosts, another
PTHrPB gene that shares 67% homology with PTHrPA
in pufferfish, Takifugu rubripes, has been found. The mature PTHrPAs of the pufferfish, sea
bream, and European flounder comprise 126, 125, and
129 aa, respectively, and share approximately 90%
sequence similarity. Although the total amino acid identity among the teleost and mammalian PTHrPs is low
(~36%), it is higher (~60%) in the N-terminal region. Eight of the first 13 residues of the human PTHrP are
identical to those in PTH . In PTHrP as well
as PTH, the first 34 aa have the structural requirements
for full PTHrP biological activity. A comparison of the
C-terminal region of PTHrPs reveals it to be much shorter
in fish than in tetrapods.![Structure of PTHRP Structure of PTHRP](/NewsImg/2022-06-22/6379149201028606598879403.jpg)
![Structure of PTHRP Structure of PTHRP](/NewsImg/2022-06-22/6379149201028606598879403.jpg)
Mammalian PTHrPs: Mr. ~17 kDa. Soluble in water,
and stable in solution at pH 4.8. To prevent enzymatic
degradation, plasma samples should be collected in
EDTA-containing tubes. Precooling the sampling tubes
and the addition of protease inhibitors further improve
the stability.
The human PTHrP gene has been located on chromosome 12 (12p11.22). The human PTHrP gene has eight
exons and seven introns, and produces several splice variants encoding mature proteins with 139, 141, and 173 aa4. In the chicken, two different mRNA isoforms encoding mature proteins with 139 and 141 aa
were found while the mouse and rat genes encode only
a single isoform. On the other hand, there
is a high similarity of the organization of the pufferfish
pthrp gene to the human PTH, chicken pth, and pufferfish
pth genes, having three exons spanning a 2.25-kb region.
Increasing Ca2+ concentrations stimulate PTHrP
secretion via CaSR in a number of normal and cancerous
cell types. CaSR is important in the modulation of
PTHrP secretion for the maintenance of the placentalfetal Ca2+ transport. In addition, the PTHrP gene
contains consensus regulatory motifs for cAMP, 1,25-
dihydroxy vitamin D3 (1,25(OH)2D3), and glucocorticoids. Dexamethasone, vitamin D, cortisol, estrogens,
and androgens have been shown to inhibit PTHrP production in vitro.
PTH1R, but not PTH2R, is activated by PTHrP. The
organization of the PTH1R gene is conserved in three
mammalian species: the rat, human, and mouse. As
described in the PTH section, PTH1R interacts with the
first 34 aa of the N-termini of both PTH and PTHrP.1 Zebrafish and other teleosts possess a third receptor, PTH3R,
which may be a result of the duplication of PTH1R. Kd in the human kidney plasma membrane,
canine kidney plasma membrane, and chick bone cell
membrane is 1–5 nM.
PTHrP (1–36) as well as PTH (1–34) are thought to
interact with the PTH1R through distinct binding and
activating domains. PTH (1–14) and PTH (1–21) analogs
show high-affinity binding and efficient activation of the
PTH1R. [Leu11, D-Trp12] PTHrP (7–34) and [Ile5
, Trp23] PTHrP
(5–36) bind with high affinity but are devoid of signaling
activity. The substitution or modification of the second
valine in PTH (1–34) or PTHrP (1–36) with a bulky
amino acid or an amino acid derivative (Trp, Arg, or
Bpa) also results in the generation of potent
antagonists.
PTHrP is known to be a critical regulator of cellular
and organ growth, development, migration, differentiation, survival, and epithelial calcium ion transport. In
mammals, judging from the distribution and expression
of mRNA, PTHrP has a greater importance in early development, which determines the rate of chondrogenesis
and structure mineralization. In teleosts, on the other
hand, the possible involvement of PTHrP in the process
of expansion and relaxation of the organs was suggested. In terrestrial vertebrates, PTHrP acts as a paracrine or autocrine regulator. While high concentrations
(0.4–1.2 nM) in the blood of fish predict a classical endocrine function, to date no PTHrP-producing gland has
been clearly identified in fish.
This was the first hormone isolated as a hypercalcemic
factor involved in the humoral hypercalcemia of malignancy.
PTHrP is a drug target for osteoporosis. The existence of a PTH-like factor in cancers has been
reported. It was isolated in 1987 from a human lung cancer cell line. A second PTHrP gene, pPTHrPB, was first
identified in the pufferfish genome. In teleosts, two
PTHrP (PTHrPA and PTHrPB) appear to be derived by
the teleost-specific third round genome duplication.
Plasma PTHrP levels have been used for the differential diagnosis of humoral HHM based on a secreted
humoral bone resorption factor and a judgment of its
curative effect from various tumors. The plasma PTHrP concentration is routinely measured to diagnose malignant tumors (including lung,
esophageal, oral, head and neck, uterine, breast, pancreatic, ovarian, hepatocellular, kidney, and bladder cancers). It has been noted that specimens for PTHrP
testing are collected according to the requirements given
by the referral laboratory.
PROMPT×
PROMPT
The What'sApp is temporarily not supported in mainland China
The What'sApp is temporarily not supported in mainland China
Cancel
Determine