GENERATION OF DIVERSITY
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.)
Alberts B, Watson JD, Bray D, et al. Molecular biology of the cell. New York: Garland Publishing, 1994.
Matsudaira P, Berk A, Zipursky L, et al. Molecular cell biology. New York: WH Freeman Co, 1999.
Lewin BM. Genes VII. New York: Oxford University Press, 1999.
Newport JW, Douglass JF. The nucleus: structure, function, and dynamics. Annu Rev Biochem 1987; 56:535.
Chin WW. Organization and expression of glycoprotein hormone genes. In: Imura H, ed. The pituitary gland. New York: Raven Press, 1985:164.
Eipper BA, Mains RE, Glembotski CC. Identification in pituitary tissue of a peptide alpha-amidation activity that acts on glycine-extended peptides and requires molecular oxygen, copper, and ascorbic acid. Proc Natl Acad Sci U S A 1983; 80:5144.
Bradbury AF, Finnie MDA, Smyth DG. Mechanism of C-terminal amide formation by pituitary enzymes. Nature 1982; 298:686.
Gilbert W. Why genes in pieces? Nature 1978; 271:501.
Sudhoff TC, Russell DW, Goldstein JL, et al. Cassette of eight exons shared by genes for LDL receptor and EGF receptor. Science 1985; 228:893.
Nevins JR. The pathway of eukaryotic mRNA formation. Annu Rev Biochem 1983; 52:441.
Darnell JE Jr. Variety in the level of gene control in eukaryotic cells. Nature 1982; 297:365.
Rowley A, Dowell SJ, Diffley FX. Recent developments in the initiation of chromosomal DNA replication: a complex picture emerges. Biochim Biophys Acta 1994; 1217:239.
Albright SR, Tjian R. TAFs revisited: more data reveal new twists and confirm old ideas. Gene 2000; 242:1.
Zawel L, Reinberg D. Advances in RNA polymerase II transcription. Curr Opin Cell Biol 1992; 4:488.
Pugh BF, Tjian R. Diverse transcriptional functions of the multisubunit eukaryotic TFIID complex. J Biol Chem 1992; 267:679.
Conaway RC, Conaway JW. General initiation factors for RNA polymerase II. Annu Rev Biochem 1993; 62:161.
Busby S, Ebright RH. Promotor structure, promotor recognition, and transcription activation in prokaryocytes. Cell 1994; 79:743.
Ptashne M. Gene regulation by proteins acting nearby and at a distance. Nature 1986; 322:697.
Walker MD, Edlund T, Boulet AM, Rutter WJ. Cell-specific expression controlled by the 5′-flanking region of insulin and chymotrypsin genes. Nature 1983; 306:557.
Edlund T, Walker MD, Barr PJ, Rutter WJ. Cell-specific expression of the rat insulin gene: evidence for role of two distinct 5′-flanking elements. Science 1985; 230:912.
Platt T. Transcription termination and the regulation of gene expression. Annu Rev Biochem 1986; 55:339.
Brawerman G. Determinants of messenger RNA stability. Cell 1987; 48:5.
Shatkin AJ. mRNA cap binding proteins: essential factors for initiating translocation. Cell 1985; 40:223.
Padgett RA, Grabowski PJ, Konarska MM, et al. Splicing of messenger RNA precursors. Annu Rev Biochem 1986; 55:1119.
Sharp PA. Splicing of messenger RNA precursors. Science 1987; 253:766.
Keller W. The RNA lariat: a new ring to the splicing of mRNA precursors. Cell 1984; 39:423.
Andreadis A, Gallego ME, Nadal-Ginard B. Generation of protein isoform diversity by alternative splicing: mechanistic and biological implications. Annu Rev Cell Biol 1987; 3:207.
Weis K. Importins and exportins: how to get in and out of the nucleus. Trends Biol Sci 1998; 23:185.
Pelletier J, Sonenberg N. Insertion mutagenesis to increase secondary structure within the 5′-noncoding region of a eucaryotic mRNA reduces translational efficiency. Cell 1985; 40:515.
Darveau A, Pelletier J, Sonenberg A. Differential efficiencies of in vitro translation of mouse cmyc transcript differing in the 5′-untranslated region. Proc Natl Acad Sci U S A 1985; 82:2315.
Shaw G, Kamen R. A conserved AU sequence from the 3′-untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 1986; 46:659.
Nielsen DA, Shapiro DJ. Insights into hormonal control of messenger RNA stability. Mol Endocrinol 1990; 4:953.
Atwater JA, Wisdom R, Verma IM. Regulated mRNA stability. Annu Rev Genet 1990; 24:519.
Kozak M. Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. Nucleic Acids Res 1984; 12:857.
Kozak M. Selection of initiation sites by eucaryotic ribosomes: effect of inserting AUG triplets upstream from the coding sequence for preproinsulin. Nucleic Acids Res 1984; 12:3873.
Kozak M. Bifunctional messenger RNAs in eukaryotes. Cell 1986; 47:481.
Von Heijne G. A new method for predicting signal sequence cleavage sites. Nucleic Acids Res 1986; 14:4683.
Gierasch LM. Signal sequences. Biochemistry 1989; 28:1.
Walter P, Gilmore R, Blobel G. Protein translocation across the endoplasmic reticulum. Cell 1984; 38:5.
Wickner WT, Lodish HF. Multiple mechanisms of protein insertion into and across membranes. Science 1985; 230:400.
Wiedmann M, Kurzchalia TV, Hartmann E, Rapoport TA. A signal sequence receptor in the endoplasmic reticulum membrane. Nature 1987; 328:830.
Dunphy WG, Rothman JE. Compartmental organization of the Golgi stack. Cell 1985; 42:13.
Mellman I, Warren G. The road taken: past and future foundations of membrane traffic. Cell 2000; 100:99.
Griffiths G, Simons K. The trans Golgi network: sorting at the exit site of the Golgi complex. Science 1986; 234:438.
Kornfeld R, Kornfeld S. Assembly of asparagine-linked oligosaccharides. Annu Rev Biochem 1985; 54:631.
Dice JF. Molecular determinants of protein half-lives in eukaryotic cells. FASEB J 1987; 1:349.
Sanders SL, Schekman R. Polypeptide translocation across the endoplasmic reticulum membrane. J Biol Chem 1992; 267:13791.
Kornfeld S. Trafficking of lysosomal enzymes in normal and disease states. J Clin Invest 1986; 77:1.
Munro S. Pelham HRB. A C-terminal signal prevents secretion of lumenal ER proteins. Cell 1987; 48:899.
Munro S, Pelham HRB. An HSP70-like protein in the ER: identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell 1986; 46:291.
Johnson LM, Bankaitis VA, Emr SD. Distinct sequence determinants direct intracellular sorting and modification for a yeast vacuolar protease. Cell 1987; 48:875.
Valls LA, Hunter CP, Rothman JH, Stevens TH. Protein sorting in yeast: the localization determinant of yeast vacuolar carboxypeptide Y residues in the propeptide. Cell 1987; 48:887.
Moore HH, Kelly RB. Re-routing of a secretory protein by fusion with human growth hormone sequences. Nature 1986; 321:443.
Kelly RB, Grote E. Protein targeting in the neuron. Annu Rev Neurosci 1993; 16:95.
Burgess TL, Kelly RB. Constitutive and regulated secretion of proteins. Annu Rev Cell Biol 1987; 3:243.
Loh YP, Snell CR, Cool DR. Receptor-mediated targeting of hormones to secretory granules. Role of carboxypeptidase E. Trends Endocrinol Metab 1997; 8:130.
Tooze J, Tooze SA. Clathrin-coated vesicular transport of secretory proteins during the formation of ACTH-containing secretory granules in AtT-20 cells. J Cell Biol 1986; 103:839.
Orci L, Ravazzola M, Storch M-J, et al. Proteolytic maturation of insulin is a post-Golgi event which occurs in acidifying clathrin-coated secretory vesicles. Cell 1987; 49:865.
Mellman I, Fuchs R, Helenius A. Acidification of the endocytic and exocytic pathways. Annu Rev Biochem 1986; 55:663.
Hong W, Tang BL. Protein trafficking along the exocytotic pathway. Bioas-says 1993; 15:231.
Gerdes HH, Glombik MM. Signal-mediated sorting to the regulated pathway of protein secretion. Anat Anz 1999; 181:447.
Inoue K, Kurosumi K. Ultrastructural immunocytochemical localization of LH and FSH in the pituitary of the untreated male rat. Cell Tissue Res 1984; 235:77.
Gullberg U, Bengtsson N, Bulow E, et al. Processing and targeting of granule proteins in human neutrophils. J Immunol Methods 1999; 232:201.
DeLisle RC, Williams IA. Regulation of membrane fusion in secretory exocytosis. Annu Rev Physiol 1986; 48:225.
Thomas G, Thorne BA, Hruby DE. Gene transfer technique to study neuropeptide processing. Annu Rev Physiol 1988; 50:323.
Yamamoto KR. Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet 1985; 19:209.
Shupnik MA, Chin WW, Habener JF, Ridgway EC. Transcriptional regulation of the thyrotropin subunit genes by thyroid hormone. J Biol Chem 1985; 260:2900.
Larsen PR, Harney JW, Moore DD. Sequences required for cell type specific thyroid hormone regulation of rat growth hormone promoter activity. J Biol Chem 1986; 261:14373.
Wright PA, Crew MD, Spindler SR. Discrete positive and negative thyroid hormone-responsive transcription regulatory elements of the rat growth hormone gene. J Biol Chem 1987; 262:5659.
Flug F, Copp RP, Casanova J, et al. Cis-acting elements of the rat growth hormone gene which mediate basal and regulated expression by thyroid hormone. J Biol Chem 1987; 262:6373.
Jantzen HM, Strahle U, Gloss B, et al. Cooperativity of glucocorticoid response elements located far upstream of the tyrosine aminotransferase gene. Nature 1987; 49:29.
Weinberger C, Thompson CC, Ong ES, et al. The c-erb-A gene encodes a thyroid hormone receptor. Nature 1986; 324:64 1.
Green S, Chambon P. A super family of potentially oncogenic hormone receptors. Nature 1986; 324:615.
Brown DD. The role of stable complexes that repress and activate eucaryotic genes. Cell 1984; 37:359.
von Hippel PH, Bear DG, Morgan WD, McSwiggen JA. Protein-nucleic acid interactions in transcription: a molecular analysis. Annu Rev Biochem 1984; 53:389.
Harrison SC. A structural taxonomy of DNA-binding domains. Nature 1991; 353:715.
Pabo CO. Transcription factors: structural families and principles of DNA recognition. Annu Rev Biochem 1992; 61:1053.
Murdoch GH, Franco R, Evans RM, Rosenfeld RG. Polypeptide hormone regulation of gene expression. Thyrotropin-releasing hormone rapidly stimulates both transcription of the prolactin and the phosphorylation of a specific nuclear protein. J Biol Chem 1983; 258:15329.
Montminy MR, Sevarino KA, Wagner JA, et al. Identification of a cyclic AMP responsive element within the rat somatostatin gene. Proc Natl Acad Sci U S A 1986; 83:6682.
Hunter T, Karin M. The regulation of transcription by phosphorylation. Cell 1992; 70:375.
Habener JF. Cyclic AMP response element binding proteins: a cornucopia of transcription factors. Mol Endocrinol 1990; 4:1087.
Kadonaga JT, Tjian R. Affinity purification of sequence-specific DNA-binding proteins. Proc Natl Acad Sci U S A 1986; 83:5889.
Brent R. Repression of transcription in yeast. Cell 1985; 42:3.
Diamond MI, Miner JN, Yoshinaga SK, Yamamoto KR. Transcriptional factor interactions: selectors of positive and negative regulation from a single DNA element. Science 1990; 249:1266.
Guarente L. Yeast promoters: positive and negative elements. Cell 1984; 36:799.
Jones NC. Negative regulation of enhancers. Nature 1986; 321:202.
Maniatis T, Goodbourn S, Fischer JA. Regulation of inducible and tissue-specific gene expression. Science 1987; 236:1237.
Yanofsky C. Transcription attenuation. J Biol Chem 1988; 263:609.
Brock ML, Shapiro DJ. Estrogen stabilizes vitellogenin mRNA against cytoplasmic degradation. Cell 1983; 34:207.
Guyette WA, Matusik RJ, Rosen JM. Prolactin-mediated transcriptional and post-transcriptional control of casein gene expression. Cell 1979; 17:1013.
Krane IM, Spindel ER, Chin WW. Thyroid hormone decreases the stability and the poly(A) tract length of rat thyrotropin -subunit messenger RNA. Mol Endocrinol 1991; 5:469.
Koenig RJ, Lazar MA, Hodin RA, et al. Inhibition of thyroid hormone action by a non-hormone binding cerbA protein generated by alternative mRNA splicing. Nature 1989; 337:659.
Chew SL. Alternative splicing of mRNA as a mode of endocrine regulation. Trends Endocrinol Metab 1997; 8:405.
Douglass J, Civelli O, Herbert E. Polyprotein gene expression: generation of diversity of neuroendocrine peptides. Annu Rev Biochem 1984; 53:665.
Wilson HE, White A. Prohormones: their clinical relevance. Trends Endocrinol Metab 1998; 9:396.