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Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins

Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins
Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins
BACKGROUND: CtBP1 and CtBP2 are transcriptional co-repressors that modulate the activity of a large number of transcriptional repressors via the recruitment of chromatin modifiers. Many CtBP-regulated proteins are involved in pathways associated with tumorigenesis, including TGF-beta and Wnt signalling pathways and cell cycle regulators such as RB/p130 and HDM2, as well as adenovirus E1A. CtBP1 and CtBP2 are highly similar proteins, although evidence is emerging that their activity can be differentially regulated, particularly through the control of their subcellular localisation. CtBP2s from diverse species contain a unique N-terminus, absent in CtBP1 that plays a key role in controlling the nuclear-cytoplasmic distribution of the protein.

RESULTS: Here we show that amino acids (a.a.) 4-14 of CtBP2 direct CtBP2 into an almost exclusively nuclear distribution in cell lines of diverse origins. Whilst this sequence contains similarity to known nuclear localisation motifs, it cannot drive nuclear localisation of a heterologous protein, but rather has been shown to function as a p300 acetyltransferase-dependent nuclear retention sequence. Here we define the region of CtBP2 required to co-operate with a.a. 4-14 to promote CtBP2 nuclear accumulation as being within a.a. 1-119. In addition, we show that a.a. 120-445 of CtBP2 can also promote CtBP2 nuclear accumulation, independently of a.a. 4-14. Finally, CtBP1 and CtBP2 can form heterodimers, and we show that the interaction with CtBP2 is one mechanism whereby CtBP1 can be recruited to the nucleus.

CONCLUSION: Together, these findings represent key distinctions in the regulation of the functions of CtBP family members that may have important implications as to their roles in development, and cell differentiation and survival.
e1a protein, repression, transformation, nuclear-localization, negative modulation, binding-protein, cellular phosphoprotein, molecular-cloning, protein, development, transcriptional corepressor, survival, membrane fission
Bergman, Lee M.
a1afd196-1202-4f26-a256-4d1257f39a8c
Morris, Laila
009caa39-b9fa-4521-b175-987cbe64be94
Darley, Matthew
7be23780-a781-4dd4-a74c-f5affbb79521
Mirnezami, Alexander H.
b3c7aee7-46a4-404c-bfe3-f72388e0bc94
Gunatilake, Samal C.
a197fae4-7704-4992-b248-f985e4942aec
Blaydes, Jeremy P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
Bergman, Lee M.
a1afd196-1202-4f26-a256-4d1257f39a8c
Morris, Laila
009caa39-b9fa-4521-b175-987cbe64be94
Darley, Matthew
7be23780-a781-4dd4-a74c-f5affbb79521
Mirnezami, Alexander H.
b3c7aee7-46a4-404c-bfe3-f72388e0bc94
Gunatilake, Samal C.
a197fae4-7704-4992-b248-f985e4942aec
Blaydes, Jeremy P.
e957f999-fd91-4f77-ad62-5b4ef069b15b

Bergman, Lee M., Morris, Laila, Darley, Matthew, Mirnezami, Alexander H., Gunatilake, Samal C. and Blaydes, Jeremy P. (2006) Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins. BMC Cell Biology, 7 (35). (doi:10.1186/1471-2121-7-35).

Record type: Article

Abstract

BACKGROUND: CtBP1 and CtBP2 are transcriptional co-repressors that modulate the activity of a large number of transcriptional repressors via the recruitment of chromatin modifiers. Many CtBP-regulated proteins are involved in pathways associated with tumorigenesis, including TGF-beta and Wnt signalling pathways and cell cycle regulators such as RB/p130 and HDM2, as well as adenovirus E1A. CtBP1 and CtBP2 are highly similar proteins, although evidence is emerging that their activity can be differentially regulated, particularly through the control of their subcellular localisation. CtBP2s from diverse species contain a unique N-terminus, absent in CtBP1 that plays a key role in controlling the nuclear-cytoplasmic distribution of the protein.

RESULTS: Here we show that amino acids (a.a.) 4-14 of CtBP2 direct CtBP2 into an almost exclusively nuclear distribution in cell lines of diverse origins. Whilst this sequence contains similarity to known nuclear localisation motifs, it cannot drive nuclear localisation of a heterologous protein, but rather has been shown to function as a p300 acetyltransferase-dependent nuclear retention sequence. Here we define the region of CtBP2 required to co-operate with a.a. 4-14 to promote CtBP2 nuclear accumulation as being within a.a. 1-119. In addition, we show that a.a. 120-445 of CtBP2 can also promote CtBP2 nuclear accumulation, independently of a.a. 4-14. Finally, CtBP1 and CtBP2 can form heterodimers, and we show that the interaction with CtBP2 is one mechanism whereby CtBP1 can be recruited to the nucleus.

CONCLUSION: Together, these findings represent key distinctions in the regulation of the functions of CtBP family members that may have important implications as to their roles in development, and cell differentiation and survival.

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Published date: 25 September 2006
Keywords: e1a protein, repression, transformation, nuclear-localization, negative modulation, binding-protein, cellular phosphoprotein, molecular-cloning, protein, development, transcriptional corepressor, survival, membrane fission

Identifiers

Local EPrints ID: 44334
URI: http://eprints.soton.ac.uk/id/eprint/44334
PURE UUID: e08c6518-7a63-45aa-86f6-9845a0474406
ORCID for Jeremy P. Blaydes: ORCID iD orcid.org/0000-0001-8525-0209

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Date deposited: 26 Feb 2007
Last modified: 24 Sep 2019 00:50

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