Search tips
Search criteria 


Logo of narLink to Publisher's site
Nucleic Acids Res. 1986 February 25; 14(4): 1883–1902.
PMCID: PMC339580

Evolution of the casein multigene family: conserved sequences in the 5' flanking and exon regions.


The rat alpha- and bovine alpha s1-casein genes have been isolated and their 5' sequences determined. The rat alpha-, beta-, gamma- and bovine alpha s1-casein genes contain similar 5' exon arrangements in which the 5' noncoding, signal peptide and casein kinase phosphorylation sequences are each encoded by separate exons. These findings support the hypothesis that during evolution, the family of casein genes arose by a process involving exon recruitment followed by intragenic and intergenic duplication of a primordial gene. Several highly conserved regions in the first 200 base pairs of the 5' flanking DNA have been identified. Additional sequence homology extending up to 550 base pairs upstream of the CAP site has been found between the rat alpha- and bovine alpha s1-casein sequences. Unexpectedly, the 5' flanking promoter regions are conserved to a greater extent than both the entire mature coding and intron regions of these genes. These conserved 5' flanking sequences may contain potential cis regulatory elements which are responsible for the coordinate expression of the functionally-related casein genes during mammary gland development.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.6M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Hobbs AA, Richards DA, Kessler DJ, Rosen JM. Complex hormonal regulation of rat casein gene expression. J Biol Chem. 1982 Apr 10;257(7):3598–3605. [PubMed]
  • Topper YJ. Multiple hormone interactions in the development of mammary gland in vitro. Recent Prog Horm Res. 1970;26:287–308. [PubMed]
  • Guyette WA, Matusik RJ, Rosen JM. Prolactin-mediated transcriptional and post-transcriptional control of casein gene expression. Cell. 1979 Aug;17(4):1013–1023. [PubMed]
  • Blackburn DE, Hobbs AA, Rosen JM. Rat beta casein cDNA: sequence analysis and evolutionary comparisons. Nucleic Acids Res. 1982 Apr 10;10(7):2295–2307. [PMC free article] [PubMed]
  • Hobbs AA, Rosen JM. Sequence of rat alpha- and gamma-casein mRNAs: evolutionary comparison of the calcium-dependent rat casein multigene family. Nucleic Acids Res. 1982 Dec 20;10(24):8079–8098. [PMC free article] [PubMed]
  • Hennighausen LG, Sippel AE. Characterization and cloning of the mRNAs specific for the lactating mouse mammary gland. Eur J Biochem. 1982 Jun 15;125(1):131–141. [PubMed]
  • Hall L, Laird JE, Craig RK. Nucleotide sequence determination of guinea-pig casein B mRNA reveals homology with bovine and rat alpha s1 caseins and conservation of the non-coding regions of the mRNA. Biochem J. 1984 Sep 15;222(3):561–570. [PubMed]
  • Hall L, Laird JE, Pascall JC, Craig RK. Guinea-pig casein A cDNA. Nucleotide sequence analysis and comparison of the deduced protein sequence with that of bovine alpha s2 casein. Eur J Biochem. 1984 Feb 1;138(3):585–589. [PubMed]
  • Stewart AF, Willis IM, Mackinlay AG. Nucleotide sequences of bovine alpha S1- and kappa-casein cDNAs. Nucleic Acids Res. 1984 May 11;12(9):3895–3907. [PMC free article] [PubMed]
  • Jones WK, Yu-Lee LY, Clift SM, Brown TL, Rosen JM. The rat casein multigene family. Fine structure and evolution of the beta-casein gene. J Biol Chem. 1985 Jun 10;260(11):7042–7050. [PubMed]
  • Yu-Lee LY, Rosen JM. The rat casein multigene family. I. Fine structure of the gamma-casein gene. J Biol Chem. 1983 Sep 10;258(17):10794–10804. [PubMed]
  • Gupta P, Rosen JM, D'Eustachio P, Ruddle FH. Localization of the casein gene family to a single mouse chromosome. J Cell Biol. 1982 Apr;93(1):199–204. [PMC free article] [PubMed]
  • Sargent TD, Wu JR, Sala-Trepat JM, Wallace RB, Reyes AA, Bonner J. The rat serum albumin gene: analysis of cloned sequences. Proc Natl Acad Sci U S A. 1979 Jul;76(7):3256–3260. [PubMed]
  • Ruppert S, Scherer G, Schütz G. Recent gene conversion involving bovine vasopressin and oxytocin precursor genes suggested by nucleotide sequence. Nature. 1984 Apr 5;308(5959):554–557. [PubMed]
  • Kafatos FC, Jones CW, Efstratiadis A. Determination of nucleic acid sequence homologies and relative concentrations by a dot hybridization procedure. Nucleic Acids Res. 1979 Nov 24;7(6):1541–1552. [PMC free article] [PubMed]
  • Messing J. New M13 vectors for cloning. Methods Enzymol. 1983;101:20–78. [PubMed]
  • Maxam AM, Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. [PubMed]
  • Staden R. An interactive graphics program for comparing and aligning nucleic acid and amino acid sequences. Nucleic Acids Res. 1982 May 11;10(9):2951–2961. [PMC free article] [PubMed]
  • Johnson ML, Levy J, Supowit SC, Yu-Lee LY, Rosen JM. Tissue- and cell-specific casein gene expression. II. Relationship to site-specific DNA methylation. J Biol Chem. 1983 Sep 10;258(17):10805–10811. [PubMed]
  • Mercier JC, Grosclaude F, Ribadeau-Dumas B. Structure primaire de la caséine s1 -bovine. Séquence complète. Eur J Biochem. 1971 Nov 11;23(1):41–51. [PubMed]
  • Mount SM. A catalogue of splice junction sequences. Nucleic Acids Res. 1982 Jan 22;10(2):459–472. [PMC free article] [PubMed]
  • Campbell SM, Rosen JM, Hennighausen LG, Strech-Jurk U, Sippel AE. Comparison of the whey acidic protein genes of the rat and mouse. Nucleic Acids Res. 1984 Nov 26;12(22):8685–8697. [PMC free article] [PubMed]
  • Breathnach R, Chambon P. Organization and expression of eucaryotic split genes coding for proteins. Annu Rev Biochem. 1981;50:349–383. [PubMed]
  • Calos MP, Miller JH. Transposable elements. Cell. 1980 Jul;20(3):579–595. [PubMed]
  • Inouye S, Soberon X, Franceschini T, Nakamura K, Itakura K, Inouye M. Role of positive charge on the amino-terminal region of the signal peptide in protein secretion across the membrane. Proc Natl Acad Sci U S A. 1982 Jun;79(11):3438–3441. [PubMed]
  • Walter P, Blobel G. Purification of a membrane-associated protein complex required for protein translocation across the endoplasmic reticulum. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7112–7116. [PubMed]
  • Sleigh RW, Sculley TB, Mackinlay AG. The binding of beta-casein to hydroxyapatite: the effect of phosphate content and location. J Dairy Res. 1979 Apr;46(2):337–342. [PubMed]
  • Gilbert W. Why genes in pieces? Nature. 1978 Feb 9;271(5645):501–501. [PubMed]
  • Südhof TC, Goldstein JL, Brown MS, Russell DW. The LDL receptor gene: a mosaic of exons shared with different proteins. Science. 1985 May 17;228(4701):815–822. [PubMed]
  • Ohno S, Emori Y, Imajoh S, Kawasaki H, Kisaragi M, Suzuki K. Evolutionary origin of a calcium-dependent protease by fusion of genes for a thiol protease and a calcium-binding protein? Nature. 1984 Dec 6;312(5994):566–570. [PubMed]
  • Hayes TE, Dixon JE. Z-DNA in the rat somatostatin gene. J Biol Chem. 1985 Jul 5;260(13):8145–8156. [PubMed]
  • Maurer RA. Selective binding of the estradiol receptor to a region at least one kilobase upstream from the rat prolactin gene. DNA. 1985 Feb;4(1):1–9. [PubMed]
  • Searle PF, Davison BL, Stuart GW, Wilkie TM, Norstedt G, Palmiter RD. Regulation, linkage, and sequence of mouse metallothionein I and II genes. Mol Cell Biol. 1984 Jul;4(7):1221–1230. [PMC free article] [PubMed]
  • Suwa Y, Mizukami Y, Sogawa K, Fujii-Kuriyama Y. Gene structure of a major form of phenobarbital-inducible cytochrome P-450 in rat liver. J Biol Chem. 1985 Jul 5;260(13):7980–7984. [PubMed]
  • Qasba PK, Safaya SK. Similarity of the nucleotide sequences of rat alpha-lactalbumin and chicken lysozyme genes. Nature. 1984 Mar 22;308(5957):377–380. [PubMed]
  • Hamada H, Petrino MG, Kakunaga T, Seidman M, Stollar BD. Characterization of genomic poly(dT-dG).poly(dC-dA) sequences: structure, organization, and conformation. Mol Cell Biol. 1984 Dec;4(12):2610–2621. [PMC free article] [PubMed]
  • Nordheim A, Rich A. Negatively supercoiled simian virus 40 DNA contains Z-DNA segments within transcriptional enhancer sequences. Nature. 1983 Jun 23;303(5919):674–679. [PubMed]
  • Hamada H, Seidman M, Howard BH, Gorman CM. Enhanced gene expression by the poly(dT-dG).poly(dC-dA) sequence. Mol Cell Biol. 1984 Dec;4(12):2622–2630. [PMC free article] [PubMed]
  • Larsen A, Weintraub H. An altered DNA conformation detected by S1 nuclease occurs at specific regions in active chick globin chromatin. Cell. 1982 Jun;29(2):609–622. [PubMed]
  • McKnight SL. Functional relationships between transcriptional control signals of the thymidine kinase gene of herpes simplex virus. Cell. 1982 Dec;31(2 Pt 1):355–365. [PubMed]
  • Concino M, Goldman RA, Caruthers MH, Weinmann R. Point mutations of the adenovirus major late promoter with different transcriptional efficiencies in vitro. J Biol Chem. 1983 Jul 10;258(13):8493–8496. [PubMed]
  • Dierks P, van Ooyen A, Mantei N, Weissmann C. DNA sequences preceding the rabbit beta-globin gene are required for formation in mouse L cells of beta-globin RNA with the correct 5' terminus. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1411–1415. [PubMed]
  • Miyata T, Hayashida H, Kikuno R, Hasegawa M, Kobayashi M, Koike K. Molecular clock of silent substitution: at least six-fold preponderance of silent changes in mitochondrial genes over those in nuclear genes. J Mol Evol. 1982;19(1):28–35. [PubMed]
  • Soares MB, Schon E, Henderson A, Karathanasis SK, Cate R, Zeitlin S, Chirgwin J, Efstratiadis A. RNA-mediated gene duplication: the rat preproinsulin I gene is a functional retroposon. Mol Cell Biol. 1985 Aug;5(8):2090–2103. [PMC free article] [PubMed]
  • Dynan WS, Tjian R. The promoter-specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter. Cell. 1983 Nov;35(1):79–87. [PubMed]
  • McKnight SL, Kingsbury RC, Spence A, Smith M. The distal transcription signals of the herpesvirus tk gene share a common hexanucleotide control sequence. Cell. 1984 May;37(1):253–262. [PubMed]
  • Williams L, McDonald C, Higgins S. Sequence organisation of rat seminal vesicle F gene: location of transcriptional start point and sequence comparison with six other androgen-regulated genes. Nucleic Acids Res. 1985 Feb 11;13(3):659–672. [PMC free article] [PubMed]
  • Davidson EH, Jacobs HT, Britten RJ. Very short repeats and coordinate induction of genes. Nature. 1983 Feb 10;301(5900):468–470. [PubMed]
  • Donahue TF, Daves RS, Lucchini G, Fink GR. A short nucleotide sequence required for regulation of HIS4 by the general control system of yeast. Cell. 1983 Jan;32(1):89–98. [PubMed]
  • Pelham HR. A regulatory upstream promoter element in the Drosophila hsp 70 heat-shock gene. Cell. 1982 Sep;30(2):517–528. [PubMed]
  • Rosen JM, O'Neal DL, McHugh JE, Comstock JP. Progesterone-mediated inhibition of casein mRNA and polysomal casein synthesis in the rat mammary gland during pregnancy. Biochemistry. 1978 Jan 24;17(2):290–297. [PubMed]
  • Scheidereit C, Geisse S, Westphal HM, Beato M. The glucocorticoid receptor binds to defined nucleotide sequences near the promoter of mouse mammary tumour virus. Nature. 1983 Aug 25;304(5928):749–752. [PubMed]
  • von der Ahe D, Janich S, Scheidereit C, Renkawitz R, Schütz G, Beato M. Glucocorticoid and progesterone receptors bind to the same sites in two hormonally regulated promoters. Nature. 1985 Feb 21;313(6004):706–709. [PubMed]
  • Jost JP, Seldran M, Geiser M. Preferential binding of estrogen-receptor complex to a region containing the estrogen-dependent hypomethylation site preceding the chicken vitellogenin II gene. Proc Natl Acad Sci U S A. 1984 Jan;81(2):429–433. [PubMed]
  • Cato AC, Geisse S, Wenz M, Westphal HM, Beato M. The nucleotide sequences recognized by the glucocorticoid receptor in the rabbit uteroglobin gene region are located far upstream from the initiation of transcription. EMBO J. 1984 Dec 1;3(12):2771–2778. [PubMed]
  • Karin M, Haslinger A, Holtgreve H, Richards RI, Krauter P, Westphal HM, Beato M. Characterization of DNA sequences through which cadmium and glucocorticoid hormones induce human metallothionein-IIA gene. Nature. 1984 Apr 5;308(5959):513–519. [PubMed]
  • Renkawitz R, Schütz G, von der Ahe D, Beato M. Sequences in the promoter region of the chicken lysozyme gene required for steroid regulation and receptor binding. Cell. 1984 Jun;37(2):503–510. [PubMed]
  • Slater EP, Rabenau O, Karin M, Baxter JD, Beato M. Glucocorticoid receptor binding and activation of a heterologous promoter by dexamethasone by the first intron of the human growth hormone gene. Mol Cell Biol. 1985 Nov;5(11):2984–2992. [PMC free article] [PubMed]
  • Payvar F, DeFranco D, Firestone GL, Edgar B, Wrange O, Okret S, Gustafsson JA, Yamamoto KR. Sequence-specific binding of glucocorticoid receptor to MTV DNA at sites within and upstream of the transcribed region. Cell. 1983 Dec;35(2 Pt 1):381–392. [PubMed]
  • Charnay P, Treisman R, Mellon P, Chao M, Axel R, Maniatis T. Differences in human alpha- and beta-globin gene expression in mouse erythroleukemia cells: the role of intragenic sequences. Cell. 1984 Aug;38(1):251–263. [PubMed]
  • Merrill GF, Hauschka SD, McKnight SL. tk Enzyme expression in differentiating muscle cells is regulated through an internal segment of the cellular tk gene. Mol Cell Biol. 1984 Sep;4(9):1777–1784. [PMC free article] [PubMed]
  • Grosschedl R, Baltimore D. Cell-type specificity of immunoglobulin gene expression is regulated by at least three DNA sequence elements. Cell. 1985 Jul;41(3):885–897. [PubMed]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press