Trends in Genetics
Volume 14, Issue 5, 1 May 1998, Pages 178-183
Journal home page for Trends in Genetics

Conjunction dysfunction: CBP/p300 in human disease

https://doi.org/10.1016/S0168-9525(98)01438-3Get rights and content

Abstract

CBP and its homolog p300 are large nuclear molecules that coordinate a variety of transcriptional pathways with chromatin remodeling. They interact with transcriptional activators as well as repressors, direct chromatin-mediated transcription, function in TP53-mediated apoptosis, and participate in terminal differentiation of certain tissue types. Recent evidence suggests that the demand for CBP/p300 is greater than the supply, and that competition for CBP/p300 might play an important role in cell growth regulation. Alterations of the human CBP gene have been implicated in hematological malignancies as well as in congenital malformation and mental retardation. Likewise, the p300 gene has been recently implicated in leukemia and mutations in both alleles have been observed in gastric and colorectal carcinomas. The role of these proteins in human disease coupled with biochemical evidence suggests that CBP and p300 are tumor suppressor proteins essential in cell-cycle control, cellular differentiation and human development.

Section snippets

CBP and p300

CBP is an evolutionarily highly conserved protein. The human CBP cDNA shares 89% homology at the DNA level with its murine homolog, while at the protein level the two CBPs are 95% identical[1]. Likewise, CBP orthologs in organisms as diverse as Drosophila and Caenorhabditis elegans, also show striking similarity to their human counterpart, including all known functional domains[2].

CBP is also closely related to p300: the proteins are 63% identical at the amino-acid level. Greater similarity is

CBP and p300 are transcriptional conjunctions

It has become increasingly apparent that CBP/p300 are focal points of multiple protein–protein interactions, to the extent that CBP/p300 have earned a reputation for being `promiscuous'[7]. Indeed, CBP and p300 are extremely versatile in their ability to bridge DNA-binding factors and basal transcription machinery physically, resulting in transcriptional transactivation[8]. These two co-factors make contact with and connect the functions of so many well-studied proteins that the list reads like

CBP/p300 and cell growth regulation

The decision of a cell to grow, differentiate or undergo apoptosis depends not only on the signals it receives from external sources, but more importantly, it depends on its unique response to those signals. Although the exact role of CBP/p300 in regulating the behavior of a cell remains unknown, several lines of evidence suggest that CBP/p300 are negative regulators of the cell cycle (Fig. 3). For example, mutated E1A proteins that cannot bind members of the retinoblastoma protein (RB1) family

CBP/p300 in development

The first indication that CBP/p300 might be implicated in embryogenesis came when researchers found that inactivating germline mutations of one CBP allele causes the Rubinstein–Taybi syndrome (RTS)[28]. This congenital disease is characterized by mental retardation, craniofacial abnormalities, and broad big toes and thumbs. Subsequent western blot analyses using anti-CBP antibodies detected reduced levels of CBP in cell lines generated from RTS patient lymphocytes, suggesting that

CBP/p300 in human cancers

Two lines of clinical evidence suggest that CBP/p300 function as tumor suppressor proteins. Firstly, RTS patients have an increased predisposition to cancer[37]. The higher prevalence of cancer in RTS patients fits the `two-hit' hypothesis for tumor suppressor proteins, although no data have yet been obtained as to whether the unaffected CBP allele is somatically mutated in RTS patient tumors. Secondly, bi-allelic inactivating somatic mutations of the p300 gene have been observed in gastric and

Concluding remarks

CBP/p300 research is now the meeting point for many fundamental questions in the fields of signal transduction, development, carcinogenesis, apoptosis and immunology. Although an astonishing amount of data delineating CBP/p300 function has been published in the last few years, there are still many unresolved issues concerning the role of CBP/p300 in disease. For example, examination of the unaffected CBP allele in both RTS tumors and hematological malignancies associated with CBP translocations

Acknowledgements

We thank R.H. Goodman and G-J.B. van Ommen for their continuous interest in the work performed in our laboratory as well as for critical reading and stimulating discussions. Supported by grants from the Dutch Cancer Society (IKW92-94 and RUL97-1502) and the Dutch Organization for Scientific Research (NWO 901-04-124).

References (60)

  • R.H. Giles

    Genomics

    (1997)
  • R. Janknecht et al.

    Curr. Biol.

    (1996)
  • V.V. Ogryzko

    Cell

    (1996)
  • H. Chen

    Cell

    (1997)
  • W. Gu et al.

    Cell

    (1997)
  • A. Imhof

    Curr. Biol.

    (1997)
  • Y. Kamei

    Cell

    (1996)
  • R.C. Aguiar

    Blood

    (1997)
  • J.D. Rowley

    Blood

    (1997)
  • T. Taki et al.

    Blood

    (1997)
  • K. Ida

    Blood

    (1997)
  • J.L. Laı̈

    Cancer Genet. Cytogenet.

    (1992)
  • J.E. Brownell

    Cell

    (1996)
  • C.A. Mizzen

    Cell

    (1996)
  • H. Akimaru

    Nature

    (1997)
  • Z. Arany

    Nature

    (1995)
  • J.R. Lundblad

    Nature

    (1995)
  • P.B. Dallas et al.

    J. Virol.

    (1997)
  • D. Barbeau

    Oncogene

    (1994)
  • N. Shikama et al.

    Trends Cell Biol.

    (1997)
  • J-S. Lee

    Genes Dev.

    (1995)
  • A.J. Bannister et al.

    Nature

    (1996)
  • X-J. Yang

    Nature

    (1996)
  • G. Jenster

    Proc. Natl. Acad. Sci. U. S. A.

    (1997)
  • T.E. Spencer

    Nature

    (1997)
  • A.E. Horvai

    Proc. Natl. Acad. Sci. U. S. A.

    (1997)
  • S.L. Costa et al.

    Cell Growth Differ.

    (1996)
  • X. Cheng et al.

    Mol. Cell. Biol.

    (1997)
  • J.A. Howe

    Proc. Natl. Acad. Sci. U. S. A.

    (1990)
  • H-G.H. Wang et al.

    J. Virol.

    (1995)
  • Cited by (366)

    • Co-condensation between transcription factor and coactivator p300 modulates transcriptional bursting kinetics

      2021, Molecular Cell
      Citation Excerpt :

      p300 and its paralog CREB-binding protein (CBP) are transcriptional coactivators that play critical roles in transcriptional control (Goodman and Smolik, 2000; Chan and La Thangue, 2001; Vo and Goodman, 2001; Dancy and Cole, 2015; Roeder, 2019). Mutations or chromosomal translocations involving p300/CBP lead to gene dysregulation and can result in diseases (Giles et al., 1998; Goodman and Smolik, 2000; Iyer et al., 2004). p300/CBP controls gene transcription by engaging in at least two regulatory mechanisms (Chan and La Thangue, 2001; Vo and Goodman, 2001; Bedford and Brindle, 2012; Lipinski et al., 2019).

    View all citing articles on Scopus
    View full text