Browsing by Author "Bose, Pinaki"
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- ItemOpen AccessBax expression measured by AQUAnalysis is an independent prognostic marker in oral squamous cell carcinoma(BioMed Central, 2012-08-01) Dort, Joseph C; Bose, Pinaki; Klimowicz, Alexander C; Kornaga, Elizabeth; Petrillo, Stephanie K; Matthews,T Wayne; Chandarana, Shamir; Magliocco, Anthony M; Brockton, Nigel T; Medicine
- ItemOpen AccessIng1 protein function in apoptosis and senescence(2010) Bose, Pinaki; Riabowol, Karl T.ING proteins act as readers and writers of the histone epigenetic code, affecting DNA repair, cellular senescence and apoptosis. My doctoral research focused upon understanding the molecular mechanisms underlying the involvement of ING1 in stress signaling. My work began with elucidating novel interacting partners of ING proteins using a cross-species (yeast, fly, and human) bioinformatics-based approach. We identified 381 proteins in a yeast interactome analysis that interacted with ING and also had human counterparts. I then biochemically confirmed the validity of the screen, showing that ING1 interacts with three proteins involved in stress signaling: p38MAPK, MEKK4 and RAD50. Our bioinformatics screen indicated that ING proteins in yeast interact with several mitochondrial proteins. Given that ING1 and p53 can functionally interact and that p53 has a transcription-independent role in apoptosis in the mitochondria, I asked if ING1 might also function outside the nucleus. We found that ING1 translocates to the mitochondria in primary fibroblasts and in established epithelial cell lines in response to apoptosis-inducing stimuli, independent of cellular p53 status. I also determined that endogenous ING1 specifically interacts with the pro-apoptotic BCL2 machinery in the mitochondria, suggesting a model in which the ING1-BAX interaction promotes mitochondrial membrane permeability, thereby promoting apoptosis. Since cellular aging is widely thought to represent a form of telomereinduced stress, I also investigated if ING1 interacted with the telomeric protein TRF2 that is involved in DNA damage and repair pathways. We found that, indeed, endogenous ING1 protein interacted with TRF2. Interestingly, TRF2 protein levels were also seen to decrease in senescent primary fibroblasts without a concomitant decrease in TRF2 mRNA levels. Further, our data provides evidence for the fact that telomere binding of TRF2 is required for its stability thereby indicating that a decrease in TRF2 levels might affect the induction of senescence caused by telomere attrition. Lastly, I characterized the DNA damage response in young versus senescent fibroblasts in which ING1 levels are altered, using 53BP1 focus formation as a surrogate marker for DNA damage. I found that decreased ability of senescent cells to process DNA damage foci correlates well with the loss of ING1 b during senescence, consistent with a role for ING1 bin DNA repair.
- ItemOpen AccessInterspecies data mining to predict novel ING-protein interactions in human(BioMed Central, 2008) Gordon, Paul; Soliman, Mohamed A; Bose, Pinaki; Sensen, Christoph W; Riabowol, Karl T.
- ItemOpen AccessMulti-tyrosine kinase inhibitors in preclinical studies for pediatric CNS AT/RT: Evidence for synergy with Topoisomerase-I inhibition(BioMed Central, 2011-12-29) Jayanthan, Aarthi; Bernoux, Delphine; Bose, Pinaki; Riabowol, Karl; Narendran, Aru
- ItemOpen AccessPolo-like kinase-1 (PLK-1) inhibitors as novel therapeutics in oral squamous cell carcinoma(2019-07-22) Sarkar, Subhanwita; Bose, Pinaki; Narendran, Aru; Bonni, Dr. Shirin; Childs, Sarah J.Polo-like kinase-1 (PLK-1) belongs to a family of conserved serine/threonine kinases and is an oncogenic protein in many cancers. Therefore, PLK-1 is an attractive therapeutic target and clinical trials are ongoing to test the efficacy of PLK-1 inhibitors in several cancer-types. Oral squamous cell carcinoma (OSCC) is a common head and neck cancer. OSCC is associated with frequent recurrences after initial curative therapy and overall poor prognosis. We analysed RNA sequencing data from The Cancer Genome Atlas (TCGA) and found that PLK-1 mRNA levels are elevated in OSCC compared to normal oral cavity squamous epithelium and high PLK-1 expression in OSCC is associated with worse survival. Based on these results, we tested the efficacy of PLK-1 inhibitors in a panel of ten OSCC cell lines. The PLK-1 inhibitor, volasertib effected cell death at low nanomolar concentrations in most tested OSCC cell lines but not in normal oral keratinocytes. Flowcytometry analysis showed that volasertib induces G2/M arrest in sensitive cell lines. Western blot analysis showed that levels of total PLK-1 and phospho PLK-1 were reduced after volasertib treatment in sensitive cell lines. Volasertib also triggered apoptosis confirmed by the cleavage of PARP and Caspase 3. Cell lines resistant to volasertib did not show any alteration in total PLK-1 and pPLK-1 after volasertib treatment. Post-operative radiotherapy is a common treatment modality in OSCC patients. In two OSCC cell lines that were refractory to volasertib treatment, a combination of volasertib and γ-radiation significantly lowered cell survival compared to volasertib or γ-radiation alone. Combination therapy with γ-radiation and volasertib in resistant cell lines resulted in S-phase arrest. Western blot analysis showed a significant reduction of total PLK-1 and pPLK-1 after combinatorial therapy. Apoptosis was induced in volasertib resistant cells as a result of combination therapy. Taken together, these in vitro studies establish the rationale for further investigation of volasertib efficacy in orthotopic OSCC xenograft models and clinical trials.
- ItemOpen AccessREAP: A two minute cell fractionation method(BioMed Central, 2010-11-10) Suzuki, Keiko; Bose, Pinaki; Leong-Quong, Rebecca Y. Y.; Fujita, Donald J.; Riabowol, Karl T.