Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

574
Chapter | 18 Pituitary Function
Pig FPDGEFTMQGCPECKLKENKYFSKLGAPIYQCMGCCFSRAYPTPARSKKT 50
Mouse L---D-II------------------------------------------
Rat L---DLII------------------------------------------
Goat ------M-----------------PD------------------------
Sheep ------------------------PD------------------------
Cattle ------------------------PD------------------------
Dog --------------------------------------------------
Cat --------------------------------------------------
Horse -------T-D------R-----F---V-----K--------------R--
Human APD V-D----T-Q--P---QP----L--------------L-----
* **** * ** ** ** ** *********** ** **
Cattle
Sheep
Mouse
Pig MLVPKNITSEATCCVAKAFTKATVMGNARVENHTECHCSTCYYHKS 96
Mouse ----------------------------------------------
Pig
Rat -----------------S----------------D-----------
Goat ------------------------T--V------D-----------
Sheep ---------------------------V------------------
Dog
Cattle ---------------------------V------------------
Dog ----------------------------K-----------------
Cat
Cat ----------------------------K-------------H--I
Horse ----------S--------IRV-----IKL----Q-Y-----H--I
Human ---Q--V---S------SYNRV----GFK-----A-----------
Horse
*** ** *** ****** ** * **** * ***** **
Human
FIGURE 18-7 Sequence comparison of the α -subunit for glycoprotein hormones (LH, FSH, and TSH). See the legend for
Figure 18-6 .
Goat
Rat
2002 ; Jorgensen et al. , 2004 ), and FOXL2 ( Ellsworth
et al. , 2006 ). In thyrotropes, however, expression of the
TSH β subunit precedes the expression of the α GSU.
Apart from commonly used elements the promoter of the
α GSU also contains response elements specifically used
by gonadotropes, thyrotropes, or throphoblasts ( Jorgensen
et al. , 2004 ). Also in the horse, this tissue-specific regulation
of α GSU expression is documented ( Farmerie et al. ,
1997 ). The canine α GSU has been coexpressed in a baculovirus
expression system together with the canine TSH β
gene ( Yang et al. , 2000 ). The steroidogenic factor-1 (SF-1)
has been shown in sheep to be essential for α GSU expression
( Baratta et al. , 2003 ).
b . (Pro)hormone
Translation of the mRNA results in the formation of a precursor
peptide with a molecular weight of approximately
13,500. The α -subunit has a high degree of homology among
species ( Fig. 18-7 ). The human sequence contains 92 amino
acids, rather than the 96 as found in all other species studied
so far. The shorter human sequence is due to a deletion of 12
nucleotides at the beginning of exon 3. After cleavage of the
signal peptide, five disulfide bridges are formed. Two asparagine
residues are prone to N-glycosylation, but there is also
a putative O-glycosylation site ( Fig. 18-7 ). The α-subunit is
produced in excess of the β -subunit that determines the hormone
specificity. The β -subunit formation is rate limiting in
the formation of hetero α β dimer.
2 . TSH
The thyrotropic cells of the anterior pituitary produce
thyroid-stimulating hormone (TSH), which stimulates both
the synthesis and secretion of thyroid hormone.
a . Gene Expression
The rat, human, and canine TSH gene consists of three
exons, whereas the mouse gene has five exons. Its expression
is restricted to pituitary thyrotropes. For the development
of thyrotropes, and also gonadotropes, the same
transcription factors are necessary as described for αGSU
expressing cells. For the development of specific thyrotropes,
the transcription factor Pit-1 is essential ( Dasen and
Rosenfeld, 2001 ). Expression of the TSH β gene is stimulated
by the transcription factors Pit-1 and GATA2, whereas
TSH β gene expression is suppressed by the active thyroid
hormone T 3 (Nakano et al. , 2004 ; Shupnik, 2000 ). In contrast
with the suppression of TSH β synthesis by T 3 , which is
produced within the pituitary by selective deiodination of T 4
by type 2 deiodinase (D2), TRH plays a dominant role in the
stimulation of TSH synthesis ( Nikrodhanond et al. , 2006 ).
The feline TSH has also been cloned and brought to
expression ( Rayalam et al. , 2006 ).
b . (Pro)hormone
The TSHβ chain consists of 118 amino acids and forms six
intrachain disulfide bonds ( Fig. 18-8 ). There are no free cysteine
residues, consistent with the fact that beta subunits form
a heterodimer with the α GSU noncovalently. The TSH β subunit
has an N-glycosylation site at asparagine 23 and has a
molecular weight of 18,000 after appropriate glycosylation.
The α -subunit is produced in excess of the β -subunit,
which determines the hormone specificity, and its formation
is rate limiting in the formation of the α - β dimer.
c . Secretion
The release of TSH is mainly regulated by stimulation by the
hypothalamic thyrotropin-releasing hormone (TRH) and a
strong negative feedback by thyroid hormone ( Pazos-Moura