Areas of Interest
My research focuses on how protein post-translational modifications, specially acetylation and phosphorylation, alter protein function in cancer cells. Recently we have described a molecular mechanism by which histone deacetylase inhibitors, a new class of therapeutic agents for cancer treatment, induce cell death in neuroblastoma cells.
Neuroblastoma is the most common extracranial solid tumor in children, and is often refractory to conventional therapies. Our results show that the histone deacetylase inhibitors in neuroblastoma cell target Bax, a pro-apoptotic protein. In these cells, Bax associates with Ku70, a protein that typically increases chemotherapy resistance and participates in DNA repair, in an acetylation-sensitive manner. Upon histone deacetylase inhibitor treatment, acetylated Ku70 releases Bax, allowing it to translocate to mitochondria and trigger cytochrome c release, leading to caspase-dependent cell death. The regulation of the association and dissociation of Ku70 and Bax is dependent on the level of the CREB-binding protein, CBP, which possesses acetyl transferase activity.
Our results demonstrate that Ku70, Bax, and CBP contribute to a therapeutic response to histone deacetylase inhibitors against neuroblastoma cells and identify the possibility of using these factors to predict clinical responsiveness to histone deacetylase inhibitor treatment.
Honors & Awards
1993-1996 National Research Service Award-NIH
1998-2000 Leukemia Society Special Fellow
Chrivia, J.C., Kwok, R.P.S., et al. (1993) Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365:855-859.
Kwok, R.P.S., et. al. (1994) Nuclear protein CBP is a coactivator of the transcription factor CREB, Nature 370:223-226.
Lundblad, J.R., Kwok, R.P.S., et. al. (1995) Adenoviral E1A-associated protein p300 as a functional homologue of the transcriptional co-activator CBP, Nature 374:85-88.
Kwok, R.P.S., et al. (1996) Control of cAMP-regulated enhancers by the viral transactivator Tax through CREB and the co-activator CBP. Nature 380:642-646. PMID: 8602268
Laurance, M.E., Kwok, R.P.S., et al. (1997) Differential activation of viral and cellular promoters by human T-cell lymphotropic virus-1 Tax and cAMP-responsive element modulator isoforms. J. Biol. Chem. 272:2646-2651. PMID: 9006899
Lundblad, J.L., Kwok, R.P.S., et al. (1998) The human T-cell leukemia virus-1 transcriptional activator Tax enhances CREB binding activity through interactions with the DNA minor groove. J. Biol. Chem. 273:19251-19259.
Lu Q., Hutchins, A.E., Doyle, C.M., Lundblad, J.R., and Kwok, R.P.S., Acetylation of CREB by CBP enhances CREB-dependent transactivation.
J. Biol. Chem. 278,15727-15734 (2003).
Subramanian C., Opipari A.W. Jr., Bian X., Castle V.P., and Kwok, R.P.S., Ku70 acetylation mediates Neuroblastoma cell death induced by histone deacetylase inhibitors. Proc. Natl. Acad. Sci. USA 102, 4842-4847 (2005) PMID: 15778293
Subramanian C., Opipari A.W., Castle V. P., and Kwok, R.P.S.,Histone deacetylase inhibition induces apoptosis in neuroblastoma Cell Cycle 4:1741-1743 (2005) PMID: 16294013
Kwok, R.P.S.,, Liu X., and Smith G.D. Distribution of co-activators CBP and p300 during mouse oocyte and embryo development Molecular Reproduction and Development 73:885-94 (2006) PMID: 16596650
Subramanian C., Jarzembowski J.A., Opipari A.W., Castle V.P., and Kwok, R.P.S.,CREB-binding protein mediates apoptotic effects of a histone deacetylase inhibitor, Trichostatin A, on neuroblastoma cells Neoplasia 9:495-503 (2007)