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

II. Anterior Lobe and Intermediate Lobe
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specialized hormone production. Methylation patterns
of the promoter may also strongly influence the overall
expression level ( Newell-Price, 2003 ).
Tissue-specific intracellular transcription factors play
a crucial role in the regulation, whether a gene comes to
expression. Specific binding of neurohormones from the
hypothalamus to membrane receptors of individual AL
cells will result in changes in intracellular second messenger
concentrations or activity, a process called signal transduction.
Using microarray technology important signaling
pathways for pituitary hormone expression can be revealed
( Ma et al. , 2005 ). Activation of these pathways results in
differences in phosphorylation of transcription factors that
may bind to a response element (RE) in the promoter unit.
Steroid hormones, thyroid hormone, and retinoids will,
after binding to specific cytoplasmic or nuclear localized
receptors, induce receptor binding to specific areas of the
promoter. For example, a glucocorticoid response element
(GRE) in the promoter of the gene encoding proopiomelanocortin
binds the glucocorticoid-receptor complex resulting
in inhibition of gene transcription (negative GRE).
Transcription is thus regulated by responses to extracellular
signals, which may also be derived by components of
the extracellular matrix (ECM) ( Paez-Pereda et al. , 2005 ).
After transcription has been initiated, a primary transcript
is made containing an RNA copy of the entire transcription
unit, the heteronuclear RNA (hnRNA). After
excision of the intron areas, a process called splicing, a cap
formation at the 5 end and the addition of a poly(A) tail
at the 3 end a mature mRNA is formed. Through alternative
splicing reactions, length variants of the mRNA may
ultimately result in variation of the coding sequence (see
Section II.C.1 ), changes in mRNA stability as found for
the insulin-like growth factors (IGFs), or by differences
in exon coupling even completely different peptides can
be obtained from a single gene as for instance in the gene
encoding calcitonin.
3 . Prohormone Biosynthesis, Processing, and Release
The process of peptide synthesis occurs principally on
the rough endoplasmic reticulum (RER). Messenger RNA
(mRNA), encoded by nuclear DNA, passes to cytosolic
ribosomes, whereby sequential processing of transfer
RNAs (tRNA), with their attached amino acids, the translation
process of mRNA to a peptide starts ( Fig. 18-4 ).
The beginning of the growing peptide forms a specific
signal peptide that facilitates the attachment of the translation
complex to the RER and enables the passage into
the lumen of the RER. The signal sequence of the preprohormone
is cleaved, and the remaining prohormone
undergoes several modifications as disulfide formation
and glycosylation. The peptide passes along the RER
lumen into the Golgi complex, where peptides are packaged
and released into the cytoplasm as membrane-bound
granules. During storage of these granules, the prohormone
is further processed by specific proteolytic cleavage,
C-terminal amidation, or N-terminal carboxylation.
Characteristic for proteolytic cleavage sites are pairs of the
basic amino acids arginine and lysine. The granules are
stored until the hormone is released by exocytosis. This
process involves fusion of the granule membrane with the
cell membrane.
II . ANTERIOR LOBE AND INTERMEDIATE
LOBE
A . Proopiomelanocortin-Derived Peptides
The corticotropic cells of the AL and the melanotropic
cells of the IL are both able to synthesize proopiomelanocortin
(POMC), the common prohormone for ACTH,
α -MSH, β -lipotropin, and a family of β -endorphin-related
peptides ( Fig. 18-5 ).
Signal peptide
γ 1,2 MSH
JP
MSH
CLIP
β-MSH
Enk
γ 3 MSH
ACTH
γ-END
pro-γ MSH
γ-LPH
β-END
N-POC
β-LPH
FIGURE 18-5 Schematic representation of preproopiomelanocortin (horizontal bar), with four domains: the signal peptide,
which is cleaved after entrance to the lumen of the RER; the N-terminal peptide (N-POC), containing the (pro) γ -MSH sequences
and the joining peptide (JP); the ACTH domain from which MSH and corticotropin-like intermediate lobe peptide (CLIP) is generated;
and the β -lipotropin ( β -LPH) domain, including the endorphin (END) family of peptides and a metenkephalin sequence
(Enk). Pairs of basic amino acid residues are indicated with vertical lines, representing potential sites of proteolytic cleavage. In
the AL major cleavage products are N-POC, ACTH, and β -LPH. In the IL the major products are N-POC, γ -MSH, α -MSH, and
β -endorphin.