Trends in Genetics
Conjunction dysfunction: CBP/p300 in human disease
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).
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