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A major example of the generation of diversity is the calcitonin and calcitonin gene–related peptide (CGRP) system. In this system, the C cell of the thyroid expresses a calcitonin-CGRP transcript that initially contains six exons. In the C cell, tissue-specific factors determine the use of the polyadenylation site in the fourth exon, but in the brain, transcription through the sixth exon, which encodes CGRP and the alternative polyadenylation site present in that exon, provides the alternative splicing and deletion of the fourth exon, which encodes calcitonin. The C cells express mostly calcitonin and not much CGRP; conversely, the hypothalamus produces mostly CGRP but not much calcitonin (see Chap. 53 and Fig. 53-1). Other examples of alternative splicing yielding different polypeptides include the synthesis of the alternate human growth hormone form, substance P, substance K, and protooncogenes.90,91
Alternative processing of polypeptides in a posttranslational process is important for the generation of polypeptide diversity.92,93 A major example of this is the production of ACTH and b-lipotropin from the POMC precursor (Fig. 3-16). Using the same mRNA transcript, the anterior pituitary gland produces ACTH and b-lipotropin, and the intermediate lobe of the pituitary gland performs further alternate proteolytic processing and produces b-endorphin, corticotropin-like intermediate lobe peptide (CLIP), a-melanocyte-stimulating hormone, and other products (see Chap. 16).

FIGURE 3-16. Alternative protein processing of the preproopiomelano-cortin (POMC) precursor. In the anterior pituitary gland, the single POMC precursor is processed posttranslationally to produce adreno-corticotropic hormone (ACTH) and b-lipotropin (b-LPH). However, the intermediate lobe further processes these peptides to a-melanocyte-stimulating hormone (a-MSH), corticotropin-like intermediate lobe peptide (CLIP), g-lipotropin (g-LPH), and b-endorphin. (From Douglass J, Civielli O, Herbert E. Polyprotein gene expression: generation of diversity of neuroendocrine peptides. Annu Rev Biochem 1984; 53:665.)


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