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Relaxin
TIBS -January 1983
32
Book Reviews The enchantment of relaxin* Relaxin (Advances in Experimental Medicine and Biology, Vol. 143)
edited by Ralph R. Anderson, Plenum Press, 1982. $45.00 (xii + 359 pages) ISBN 0 306 40901 1 Relaxin
edited by G. D. Bryant-Greenwood, H . D . Niall and F.C. Greenwood, Elsevier~North-Holland, 1981. Dr. 180.00 (xiv + 40l pages) ISBN 0 444 00643 5 Relaxin: Structure, Function and Evolution
edited by Bernard G. Steinetz, Christian Schwabe and Gerson Weiss, The New York Academy o f Sciences, 1982. $52.00 (vii + 246pages) ISBN 0 89766 150 8 Relaxin is a small peptide hormone discovered in 1926 by Hisaw. It has the same general chain structure as insulin, but otherwise has a very limited sequence homology. It is synthesized in the corpus luteum and evidently plays an important part in softening the cervix prior to delivery. Following its discovery by Hisaw and much subsequent investigation by other workers, there was a hiatus in relaxin research until the paper of Sherwood and O'Bryant in 1974, which describes improved methods of isolation and purification of the hormone. The importance of this work can be gauged by the publication 3 years later of pig relaxin's amino acid sequence, determined independently by Hugh Niall and Chris Schwabe and their colleagues. As a result of this research, the earlier notions based on the two chain and disulphide structure - that insuli,a and relaxin might share some structural features, were confirmed. However, the field was presented with a fascinating surprise, since the degree of homology between the two hormones was so limited and their physiological functions utterly unrelated. The three books reviewed here are an indication of the interest and activity in the relaxin field over the last 5 years, when the pig relaxin sequence was first established. These volumes are each the proceedings of research workshops. The first was held in October 1979 at the University of Missouri * Thistitle is tamousin the field;it was a misprintfor a studyon the enhancementof relaxin.
(edited by Anderson), the second in June 1980 at the University of Hawaii (BryantGreenwood et al. ), and the third in January 1981 at Santa Ynez in California (Steinetz et al. ). There are inevitable similarities in much of the work reported, occurring as it does within a space of 16 months, and often involving the same workers. The format in the books is also similar, consisting of papers (many of them short) followed by a discussion; all cover a very wide area of research. All the books are interesting, though for different reasons. In the Missouri book, there are some thoroughly useful general papers such as those on the hormone's localization and activity (by Lloyd Anderson) and on its isolation and its radioimmunoassay (Sherwood). Other papers are more interesting for historical reasons: the detection of high molecular weight precursors which indicated the existence of processing steps in biosynthesis; the early experiments on relaxin mRNA which, we now know, have led to the sequence of preprorelaxin; the first findings that relaxin is present in the non-pregnant animal, and suggestions of its having a function in the male, indicate the breadth of the early research and the incompleteness of our understanding of the hormone's functions an ignorance which still largely exists. The Hawaiian meeting contains an account and a number of anecdotes of the early days of relaxin research, mostly from Steinetz and Kroc. These enliven the technicalities which, in meetings like these, can make the papers indigestible. Between the Missouri and Hawaii meetings, the main progress was the clearer picture of the hormone's processing, the sequence determination of relaxin from the rat (Niall et al. ), and in some preliminary work on shark relaxin (Schwabe et al. ). The sequence differences between the pig and rat relaxins are striking, and are quite as large as between pig and shark relaxin. This finding has raised numerous questions about the efficacy of radioimmunoassay techniques. At a more fundamental level, it has a bearing on the evolution of the hormones, and may also explain the great variation found in the ease with which the hormone can be isolated and its differing potency in different animals. Also, the sequence variation is in marked contrast to the insulins' behaviour, and raises the question of how similar is the role of the hormone in different species.
Investigations into whether relaxin is present or not in marsupials, in tissues other than the corpus luteum (from male and female), generally indicate that it is - the significance of these findings generated a great deal of discussion. The speed of progress in the field, and its influence by the course of insulin research, is underlined by the experiments to synthesize relaxin. This work, camed out by Tregear and his colleagues, is important since it provides pure samples, undegraded by enzymatic reactivity. It also provides the means for modifying the hormone specifically and thus for exploring the relationship between its structure and function. Relaxin' s ability to soften the cartilage in the pelvic symphyses is brought about by the hormone's ability to remodel connective tissue. There is a valuable paper by Lowther on connective tissue structure and the processes associated with its assembly, ordering, and sohibilization (through enzyme action). The mechanism by which relaxin brings about these changes in connective tissue can however still only be guessed at. The Santa Ynez book has the obvious advantage of being the most recent. The volume is able to concentrate on relaxin's evolutionary aspects, its biosynthesis where there has been progress, and its mechanism of action where there have been many difficulties. Like the Hawaiian meeting, the Santa Ynez workshop was laced with a good deal of history, largely provided again by Robert Kroc whose first interest in relaxin came from Hisaw's lectures. The debates begun in the earlier meetings are seen to continue. One of the most interesting of these is on the nature of the relationship between insulin and relaxin. With the shark sequence complete, Schwabe reiterates his view that there has not been gene duplication, since the homology between relaxin and insulin does not improve with older species. One guesses that this idea was resisted vigorously, and in my view rightly. There was a clear statement that structure survives much more than sequence in evolution. It should perhaps be noted that there is at least one possible and relevant exception to this generalization. There is strong evidence for homology between proinsulin and trypsin, as noted by Steiner and others, and analysed in detail by de Haen. Interestingly enough, this seemingly outrageous proposal is supported by the structure of the insulin gene, whose intron in the connecting peptide segment allows one to match
32
Book Reviews The enchantment of relaxin* Relaxin (Advances in Experimental Medicine and Biology, Vol. 143)
edited by Ralph R. Anderson, Plenum Press, 1982. $45.00 (xii + 359 pages) ISBN 0 306 40901 1 Relaxin
edited by G. D. Bryant-Greenwood, H . D . Niall and F.C. Greenwood, Elsevier~North-Holland, 1981. Dr. 180.00 (xiv + 40l pages) ISBN 0 444 00643 5 Relaxin: Structure, Function and Evolution
edited by Bernard G. Steinetz, Christian Schwabe and Gerson Weiss, The New York Academy o f Sciences, 1982. $52.00 (vii + 246pages) ISBN 0 89766 150 8 Relaxin is a small peptide hormone discovered in 1926 by Hisaw. It has the same general chain structure as insulin, but otherwise has a very limited sequence homology. It is synthesized in the corpus luteum and evidently plays an important part in softening the cervix prior to delivery. Following its discovery by Hisaw and much subsequent investigation by other workers, there was a hiatus in relaxin research until the paper of Sherwood and O'Bryant in 1974, which describes improved methods of isolation and purification of the hormone. The importance of this work can be gauged by the publication 3 years later of pig relaxin's amino acid sequence, determined independently by Hugh Niall and Chris Schwabe and their colleagues. As a result of this research, the earlier notions based on the two chain and disulphide structure - that insuli,a and relaxin might share some structural features, were confirmed. However, the field was presented with a fascinating surprise, since the degree of homology between the two hormones was so limited and their physiological functions utterly unrelated. The three books reviewed here are an indication of the interest and activity in the relaxin field over the last 5 years, when the pig relaxin sequence was first established. These volumes are each the proceedings of research workshops. The first was held in October 1979 at the University of Missouri * Thistitle is tamousin the field;it was a misprintfor a studyon the enhancementof relaxin.
(edited by Anderson), the second in June 1980 at the University of Hawaii (BryantGreenwood et al. ), and the third in January 1981 at Santa Ynez in California (Steinetz et al. ). There are inevitable similarities in much of the work reported, occurring as it does within a space of 16 months, and often involving the same workers. The format in the books is also similar, consisting of papers (many of them short) followed by a discussion; all cover a very wide area of research. All the books are interesting, though for different reasons. In the Missouri book, there are some thoroughly useful general papers such as those on the hormone's localization and activity (by Lloyd Anderson) and on its isolation and its radioimmunoassay (Sherwood). Other papers are more interesting for historical reasons: the detection of high molecular weight precursors which indicated the existence of processing steps in biosynthesis; the early experiments on relaxin mRNA which, we now know, have led to the sequence of preprorelaxin; the first findings that relaxin is present in the non-pregnant animal, and suggestions of its having a function in the male, indicate the breadth of the early research and the incompleteness of our understanding of the hormone's functions an ignorance which still largely exists. The Hawaiian meeting contains an account and a number of anecdotes of the early days of relaxin research, mostly from Steinetz and Kroc. These enliven the technicalities which, in meetings like these, can make the papers indigestible. Between the Missouri and Hawaii meetings, the main progress was the clearer picture of the hormone's processing, the sequence determination of relaxin from the rat (Niall et al. ), and in some preliminary work on shark relaxin (Schwabe et al. ). The sequence differences between the pig and rat relaxins are striking, and are quite as large as between pig and shark relaxin. This finding has raised numerous questions about the efficacy of radioimmunoassay techniques. At a more fundamental level, it has a bearing on the evolution of the hormones, and may also explain the great variation found in the ease with which the hormone can be isolated and its differing potency in different animals. Also, the sequence variation is in marked contrast to the insulins' behaviour, and raises the question of how similar is the role of the hormone in different species.
Investigations into whether relaxin is present or not in marsupials, in tissues other than the corpus luteum (from male and female), generally indicate that it is - the significance of these findings generated a great deal of discussion. The speed of progress in the field, and its influence by the course of insulin research, is underlined by the experiments to synthesize relaxin. This work, camed out by Tregear and his colleagues, is important since it provides pure samples, undegraded by enzymatic reactivity. It also provides the means for modifying the hormone specifically and thus for exploring the relationship between its structure and function. Relaxin' s ability to soften the cartilage in the pelvic symphyses is brought about by the hormone's ability to remodel connective tissue. There is a valuable paper by Lowther on connective tissue structure and the processes associated with its assembly, ordering, and sohibilization (through enzyme action). The mechanism by which relaxin brings about these changes in connective tissue can however still only be guessed at. The Santa Ynez book has the obvious advantage of being the most recent. The volume is able to concentrate on relaxin's evolutionary aspects, its biosynthesis where there has been progress, and its mechanism of action where there have been many difficulties. Like the Hawaiian meeting, the Santa Ynez workshop was laced with a good deal of history, largely provided again by Robert Kroc whose first interest in relaxin came from Hisaw's lectures. The debates begun in the earlier meetings are seen to continue. One of the most interesting of these is on the nature of the relationship between insulin and relaxin. With the shark sequence complete, Schwabe reiterates his view that there has not been gene duplication, since the homology between relaxin and insulin does not improve with older species. One guesses that this idea was resisted vigorously, and in my view rightly. There was a clear statement that structure survives much more than sequence in evolution. It should perhaps be noted that there is at least one possible and relevant exception to this generalization. There is strong evidence for homology between proinsulin and trypsin, as noted by Steiner and others, and analysed in detail by de Haen. Interestingly enough, this seemingly outrageous proposal is supported by the structure of the insulin gene, whose intron in the connecting peptide segment allows one to match