Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins.
10.1101/gad.9.6.663
Crossref journal-article
Cold Spring Harbor Laboratory
Genes & Development (246)
Abstract

The human proto-oncogene PBX1 codes for a homolog of Drosophila extradenticle, a divergent homeo domain protein that modulates the developmental and DNA-binding specificity of select HOM proteins. We demonstrate that wild-type Pbx proteins and chimeric E2a-Pbx1 oncoproteins cooperatively bind a consensus DNA probe with HoxB4, B6, and B7 of the Antennapedia class of Hox/HOM proteins. Specificity of Hox-Pbx interactions was suggested by the inability of Pbx proteins to cooperatively bind the synthetic DNA target with HoxA10 or Drosophila even-skipped. Site-directed mutagenesis showed that the hexapeptide motif (IYPWMK) upstream of the Hox homeo domain was essential for HoxB6 and B7 to cooperatively bind DNA with Pbx proteins. Engraftment of the HoxB7 hexapeptide onto HoxA10 endowed it with robust cooperative properties, demonstrating a functional role for the highly conserved hexapeptide element as one of the molecular determinants delimiting Hox-Pbx cooperativity. The Pbx homeo domain was necessary but not sufficient for cooperativity, which required conserved amino acids carboxy-terminal of the homeo domain. These findings demonstrate that interactions between Hox and Pbx proteins modulate their DNA-binding properties, suggesting that Pbx and Hox proteins act in parallel as heterotypic complexes to regulate expression of specific subordinate genes.

Bibliography

Chang, C. P., Shen, W. F., Rozenfeld, S., Lawrence, H. J., Largman, C., & Cleary, M. L. (1995). Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins. Genes & Development, 9(6), 663–674.

Authors 6
  1. C P Chang (first)
  2. W F Shen (additional)
  3. S Rozenfeld (additional)
  4. H J Lawrence (additional)
  5. C Largman (additional)
  6. M L Cleary (additional)
References 56 Referenced 313
  1. 10.1016/0092-8674(89)90909-4 / Cell / Hox and Hom: Homologous gene clusters in insects and vertebrates. (1989)
  2. {'key': '2021111418212874000_9.6.663.2', 'first-page': '1599', 'article-title': 'Synergistic activation of transcription is mediated by the N-terminal domain of Drosophila fushi tarazu homeoprotein and can occur without DNA binding by the protein.', 'volume': '13', 'year': '1993', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / Synergistic activation of transcription is mediated by the N-terminal domain of Drosophila fushi tarazu homeoprotein and can occur without DNA binding by the protein. (1993)
  3. {'key': '2021111418212874000_9.6.663.3', 'first-page': '6941', 'article-title': 'Cooperative binding of an Ultrabithorax homeo domain protein to nearby and distant DNA sites.', 'volume': '13', 'year': '1993', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / Cooperative binding of an Ultrabithorax homeo domain protein to nearby and distant DNA sites. (1993)
  4. 10.1101/SQB.1985.050.01.078
  5. Bürglin, T.R. 1994. A comprehensive classification of homeobox genes. Guidebook to the homeobox genes (ed. D. Duboule), pp. 27–41. Oxford University Press, Oxford, UK. (10.1093/oso/9780198599395.003.0003)
  6. 10.1038/ng0892-319
  7. 10.1016/0092-8674(94)90525-8
  8. 10.1016/0092-8674(93)90463-Z
  9. 10.1016/0092-8674(88)90123-7
  10. 10.1002/j.1460-2075.1992.tb05138.x / EMBO J. / Antp-type homeodomains have distinct DNA binding specificities that correlate with their different regulatory functions in embryos. (1992)
  11. 10.1002/j.1460-2075.1994.tb06662.x / EMBO J. / The degree of variation in DNA sequence recognition among four Drosophila homeotic proteins. (1994)
  12. 10.1038/356610a0
  13. 10.1016/0925-4773(93)90045-Y
  14. 10.1146/annurev.bi.63.070194.002415
  15. 10.1016/0092-8674(94)90292-5
  16. 10.1002/j.1460-2075.1994.tb06397.x / EMBO J. / Recognition of a DNA operator by a dimer composed of two different homeodomain proteins. (1994)
  17. 10.1126/science.257.5073.1089
  18. 10.1016/0092-8674(93)90499-G
  19. 10.1038/332858a0
  20. {'key': '2021111418212874000_9.6.663.20', 'first-page': '4598', 'article-title': 'DNA-binding activities of the Drosophila melanogaster even- skipped protein are mediated by its homeo domain and influenced by protein contact.', 'volume': '8', 'year': '1988', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / DNA-binding activities of the Drosophila melanogaster even- skipped protein are mediated by its homeo domain and influenced by protein contact. (1988)
  21. 10.1016/0092-8674(90)90067-O
  22. {'key': '2021111418212874000_9.6.663.22', 'first-page': '7321', 'article-title': 'E2A expression, nuclear localization, and in vivo formation of DNA- and non-DNA-binding species during B-cell development.', 'volume': '13', 'year': '1993', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / E2A expression, nuclear localization, and in vivo formation of DNA- and non-DNA-binding species during B-cell development. (1993)
  23. Johnson, A. 1992. A combinatorial regulatory circuit in budding yeast. In Transcriptional Regulation (ed. S.L. McKnight and K.R. Yamamoto), pp. 975–1006. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.
  24. Johnson, F.B., Parker, E. and Krasnow. M.A. 1995. extradenticle protein is a selective cofactor for the Drosophila homeotics: Role of the homeodomain and YPWM motif in the interaction. Proc. Natl. Acad. Sci. (in press). (10.1073/pnas.92.3.739)
  25. 10.1016/0092-8674(90)90658-2
  26. 10.1016/0092-8674(89)90039-1
  27. 10.1016/0925-4773(90)90137-B
  28. 10.1182/blood.V80.10.2445.2445 / Blood / Homeobox genes in normal hematopoiesis and leukemia. (1992)
  29. {'key': '2021111418212874000_9.6.663.29', 'first-page': '665', 'article-title': 'Expression of HOX C homeobox genes in lymphoid cells.', 'volume': '4', 'year': '1993', 'journal-title': 'Cell Growth Diff.'} / Cell Growth Diff. / Expression of HOX C homeobox genes in lymphoid cells. (1993)
  30. {'key': '2021111418212874000_9.6.663.30', 'first-page': '1641', 'article-title': 'Fusion with E2A alters the transcriptional properties of the homeodomain protein PBX1 in t(1;19) leukemias.', 'volume': '9', 'year': '1994', 'journal-title': 'Oncogene'} / Oncogene / Fusion with E2A alters the transcriptional properties of the homeodomain protein PBX1 in t(1;19) leukemias. (1994)
  31. {'key': '2021111418212874000_9.6.663.31', 'first-page': '3938', 'article-title': 'Fusion with E2A converts the Pbx1 homeodomain protein into a constitutive transcriptional activator in human leukemias carrying the t(1;19) translocation.', 'volume': '14', 'year': '1994', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / Fusion with E2A converts the Pbx1 homeodomain protein into a constitutive transcriptional activator in human leukemias carrying the t(1;19) translocation. (1994)
  32. 10.1016/0092-8674(92)90471-N
  33. {'key': '2021111418212874000_9.6.663.33', 'first-page': '6149', 'article-title': 'PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1.', 'volume': '11', 'year': '1991', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1. (1991)
  34. {'key': '2021111418212874000_9.6.663.34', 'first-page': '8304', 'article-title': 'Transformation properties of the E2a-Pbx1 chimeric oncoprotein: Fusion with E2a is essential but the Pbx1 homeodomain is dispensible.', 'volume': '14', 'year': '1994', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / Transformation properties of the E2a-Pbx1 chimeric oncoprotein: Fusion with E2a is essential but the Pbx1 homeodomain is dispensible. (1994)
  35. 10.1002/j.1460-2075.1988.tb03328.x / EMBO J. / Isolation and sequence-specific DNA binding of the Antennapedia homeodomain. (1988)
  36. 10.1016/0092-8674(90)90657-Z
  37. 10.1101/gad.4.7.1209
  38. {'key': '2021111418212874000_9.6.663.38', 'first-page': '4532', 'article-title': 'Hox proteins have different affinities for a consensus DNA site that correlate with the positions of their genes on the hox cluster.', 'volume': '14', 'year': '1994', 'journal-title': 'Mol. Cell Biol.'} / Mol. Cell Biol. / Hox proteins have different affinities for a consensus DNA site that correlate with the positions of their genes on the hox cluster. (1994)
  39. 10.1111/j.1432-0436.1990.tb00458.x
  40. 10.1002/j.1460-2075.1994.tb06663.x / EMBO J. / Coordinate regulation of downstream genes by extradenticle and the homeotic selector proteins. (1994)
  41. 10.1016/0092-8674(93)90731-5
  42. 10.1002/j.1460-2075.1991.tb07665.x / EMBO J. / vHNF1 is a homeoprotein that activates transcription and forms heterodimers with HNF1. (1991)
  43. 10.1073/pnas.90.4.1450
  44. {'key': '2021111418212874000_9.6.663.44', 'first-page': '25', 'article-title': 'The structure and function of the homeodomain.', 'volume': '989', 'year': '1989', 'journal-title': 'Biochim. Biophys. Acta'} / Biochim. Biophys. Acta / The structure and function of the homeodomain. (1989)
  45. 10.1093/nar/19.3.539
  46. 10.1073/pnas.84.14.4914
  47. 10.1038/371429a0
  48. 10.1038/341624a0
  49. 10.1016/0092-8674(92)90186-G
  50. 10.1016/0092-8674(94)90526-6
  51. 10.1073/pnas.90.13.6061
  52. {'key': '2021111418212874000_9.6.663.52', 'first-page': '542', 'article-title': 'The Oct-1 POU domain mediates interactions between Oct-1 and other POU proteins.', 'volume': '12', 'year': '1992', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / The Oct-1 POU domain mediates interactions between Oct-1 and other POU proteins. (1992)
  53. 10.1101/gad.5.7.1309
  54. 10.1101/gad.7.11.2120
  55. 10.1126/science.8103239
  56. 10.1101/gad.8.6.732
Dates
Type When
Created 18 years, 3 months ago (June 5, 2007, 5:15 p.m.)
Deposited 1 year, 6 months ago (Feb. 14, 2024, 4:23 p.m.)
Indexed 2 days, 22 hours ago (Sept. 3, 2025, 6:33 a.m.)
Issued 30 years, 5 months ago (March 15, 1995)
Published 30 years, 5 months ago (March 15, 1995)
Published Online 30 years, 5 months ago (March 15, 1995)
Published Print 30 years, 5 months ago (March 15, 1995)
Funders 0

None

@article{Chang_1995, title={Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins.}, volume={9}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.9.6.663}, DOI={10.1101/gad.9.6.663}, number={6}, journal={Genes & Development}, publisher={Cold Spring Harbor Laboratory}, author={Chang, C P and Shen, W F and Rozenfeld, S and Lawrence, H J and Largman, C and Cleary, M L}, year={1995}, month=mar, pages={663–674} }