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• Circumscribing the clinical severity of Rubinstein-Taybi syndrome by CBP modulated genome expression
  Atif A Baig
  Published on: 9 January 2012

• Published on: 9 January 2012

  Circumscribing the clinical severity of Rubinstein-Taybi syndrome by CBP modulated genome expression

  • Atif A Baig, Medical Lecturer
  • Other Contributors:
    • 2. Rabia A, 3. Zilfalil B Alwi

  The respective article was well read by us. We agree with the precious scientific findings by the authors but at the same time we would like to recall the two very basic fundamental functions of CBP, which involve CBP as a bridging molecule and a cofactor (Montmini et al., 1986) for CREB modulated gene expression and histone acetyltransferase activity of CBP on CREB modulated gene expression (Lu et al., 2003) specificall...

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  The respective article was well read by us. We agree with the precious scientific findings by the authors but at the same time we would like to recall the two very basic fundamental functions of CBP, which involve CBP as a bridging molecule and a cofactor (Montmini et al., 1986) for CREB modulated gene expression and histone acetyltransferase activity of CBP on CREB modulated gene expression (Lu et al., 2003) specifically and on histone acetylation in general.

  This study specifically targeted lymphoid cell lines from patients with Rubinstein-Taybi syndrome but it has provided a new horizon towards defining some crucial event as the respective authors have tried to correlate the general post-transcriptional events (via histone acetylation level) with the transcriptional events (by CBP and p300 as a co- activators/cofactors). The study has given the overall status of the histone acetylation level and mutations within the CBP gene but yet unable to describe the role of these mutations in CBP specifically to any specific genes/motifs within the whole genome or in the CRE elements in the promoter region of different genes, which could play a vital role in circumscribing the clinical severity of the disease as has been in seen in a report from Sarmila et al., 2004; which stated the role in overexpressing the SMN genes associated with Spinal Muscular Atrophy. The disease shared quite similar clinical features with Rubinstein-Taybi syndrome with a vast heterogeneity.

  The transcription factors are reported to be phosphorylated by Protein Kinase K (PKA) which is dependent on increase level of cAMP. CREB has been reported to be the best linked between PKA activation and gene transcription (Montmini et al., 1986). Authors also studied p300 which has been reported to interact with many transcription factors, reflecting the role of p300 and CBP as co-activators more generally in signal integration (Goodman et al., 2000).

  Deficit in histone acetylation in cell lines in this study can be correlated to the defect in histone acetyltransferase activity of CBP in general on the whole genome but the specific effect through the invitro CREB acetylation must be considered by the respective authors by atleast the linkage analysis of the CREB induced genes in the described nine patients in this study. We assume, by doing so, the role of CREB or CRE modulated disease severity could be ruled out. We have done the same for Spinal Muscular Atrophy (data not published yet).

  Similarly, the use of histone deacetylases (HDACi)followed by the the acetylation status is too general for the entire genome. For sure, HDACi will recover the "acetyltransferase activity" of CBP but the effect of HDACi on the coactivation function of the CBP is not well explained. Any of the histone deacetylases, will increase the whole genome expression but defining the specific HDACi molecule for a specific gene is the need for decreasing and circumscribing the clinical severity of Rubinstein-Taybi syndrome. Some studies have been reported explaining the effect of HDACi in SMA which make use of several molecules (Sumner et al., 2006 and Brichta et al., 2003, Andreassi et al., 2004).

  There is a need to explore the specific genes for their epigentic control and effect in Rubinstein-Taybi syndrome therefore, further studies are needed to confirm the effect of these mutation and histone acetylation; towards defining specific genes in circumscribing the clinical severity of Rubinstein-Taybi syndrome and to develop a strategy for gene therapy.

  References:

  1. Montminy MR, Bilezikjian LM, (1987). Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature. 15;328(6126):175-8.

  2. Lu Q, Hutchins AE, Doyle CM, Lundblad JR, Kwok RP, (2003). Acetylation of cAMP-responsive element-binding protein (CREB) by CREB- binding protein enhances CREB-dependent transcription. J Biol Chem. 2;278(18):15727-34.

  3. Sarmila Majumder, Saradhadevi Varadharaj, Kalpana Ghoshal, Umrao Monani, Arthur H. M. Burghes, Samson T. Jacob, (2004). Identification of a Novel Cyclic AMP-response Element (CRE-II) and the Role of CREB-1 in the cAMP-induced Expression of the Survival Motor Neuron (SMN) Gene. The journal of biological chemistry: 279, 15: 14803-1481.

  4.Goodman RH, Smolik S, (2000). CBP/p300 in cell growth, transformation, and development. Genes Dev. 1;14(13):1553-77.

  5. Sumner CJ, (2006). Therapeutics development for spinal muscular atrophy. NeuroRx: 3:235-245.

  6. Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl FA, Raschke H, Blumcke I, Eyupoglu IY, Wirth B, (2003). Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscula

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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