Sehbanul Islam
University of Pune, NCCS, Graduate Student
Research Interests:
Research Interests:
Sequential alteration in the expression levels of cell cycle regulatory proteins is crucial for faithful cell cycle progression to maintain the cellular homeostasis. F‐box protein β‐TrCP1 is known to control the expression levels of... more
Sequential alteration in the expression levels of cell cycle regulatory proteins is crucial for faithful cell cycle progression to maintain the cellular homeostasis. F‐box protein β‐TrCP1 is known to control the expression levels of several important cell cycle regulatory proteins. However, how the function of β‐TrCP1 is regulated in spatiotemporal manner during cell cycle progression remains elusive. Here, we show that expression levels of β‐TrCP1 oscillate during cell cycle progression with a minimum level at the G1 and S phases of cell cycle. Using biochemical, flow cytometry, and immunofluorescence techniques, we found that oscillation of β‐TrCP1 expression is controlled by another F‐box protein FBXW8. FBXW8 directs the proteasomal degradation of β‐TrCP1 in MAPK pathway‐dependent manner. Interestingly, we found that the attenuation of β‐TrCP1 by FBXW8 is important for Cdc25A‐mediated cell cycle transition from G1 phase to S phase as well as DNA damage‐free progression of S phase. Overall, our study reveals the intriguing molecular mechanism and significance of maintenance of β‐TrCP1 levels during cell cycle progression by FBXW8‐mediated proteasomal degradation.
Research Interests:
Research Interests:
F-box proteins β-TrCP1 and β-TrCP2 are paralogs present in the human genome. They control several cellular processes including cell cycle and DNA damage signaling. Moreover, it is reported that they facilitate DNA damage-induced... more
F-box proteins β-TrCP1 and β-TrCP2 are paralogs present in the human genome. They control several cellular processes including cell cycle and DNA damage signaling. Moreover, it is reported that they facilitate DNA damage-induced accumulation of p53 by directing proteasomal degradation of MDM2, a protein that promotes p53 degradation. However, the individual roles of β-TrCP1 and β-TrCP2 in the genotoxic stress-induced activation of cell cycle checkpoints and DNA damage repair remain largely unknown. Here, using biochemical, molecular biology, flow cytometric, and immunofluorescence techniques, we show that β-TrCP1 and β-TrCP2 communicate during genotoxic stress. We found that expression levels of β-TrCP1 are significantly increased while levels of β-TrCP2 are markedly decreased upon induction of genotoxic stress. Further, our results revealed that DNA damage-induced activation of ATM kinase plays an important role in maintaining the reciprocal expression levels of β-TrCP1 and β-TrCP2 via the phosphorylation of β-TrCP1 at Ser158. Phosphorylated β-TrCP1 potently promotes the proteasomal degradation of β-TrCP2 and MDM2, resulting in the activation of p53. Additionally, β-TrCP1 impedes MDM2 accumulation via abrogation of its lysine 63-linked polyubiquitination by β-TrCP2. Thus, β-TrCP1 helps to arrest cells at the G2/M phase of the cell cycle and promotes DNA repair upon DNA damage through attenuation of β-TrCP2. Collectively, our findings elucidate an intriguing posttranslational regulatory mechanism of these two paralogs under genotoxic stress and revealed β-TrCP1 as a key player in maintaining the genome integrity through the attenuation of β-TrCP2 levels in response to genotoxic stress.
Research Interests:
Series of novel truncated carbocyclic nucleoside analogues have been synthesized from the versatile starting material D-ribose and their anticancer activities have been evaluated. The nucleoside analogues induced cytotoxicity in breast... more
Series of novel truncated carbocyclic nucleoside analogues have been synthesized from the versatile starting material D-ribose and their anticancer activities have been evaluated. The nucleoside analogues induced cytotoxicity in breast and ovarian cancer cell lines. These compounds are less cytotoxic to normal kidney cell line (HEK 293) as compared to the cancer cells. Among the synthesized compounds, 1b and 1d showed the better cytotoxic effect with IC50 44 and 54 μM, in MCF7 cells, respectively. These compounds inactivate the important signaling kinases AKT and mTOR and thereby induce autophagy. Collectively our observation suggests that compound 1b and 1d inhibit the cancer cell proliferation through induction of autophagy mode of cell death.
Research Interests:
Research Interests:
Although the cure of amyloid related neurodegenerative diseases, non-neuropathic amyloidogenic diseases and non-neuropathic systemic amyloidosis are appealing energetic research attempts, beneficial medication is still to be discovered.... more
Although the cure of amyloid related neurodegenerative diseases, non-neuropathic amyloidogenic diseases and non-neuropathic systemic amyloidosis are appealing energetic research attempts, beneficial medication is still to be discovered. There is a need to explore intensely stable therapeutic compounds, potent enough to restrict, disrupt or wipe out such toxic aggregates. We had performed a comprehensive biophysical, computational and cell based assay, that shows Nordihydroguaiaretic acid (NA) not only significantly inhibits heat induced hen egg white lysozyme (HEWL) fibrillation but also disaggregates preformed HEWL fibrils and reduces the cytoxicity of amyloid fibrils as well as disaggregated fibrillar species. The inhibitory potency of NA was determined by an IC50 of 26.3 μM. NA was also found to effectively inhibit human lysozyme (HL) fibrillation. NA interferes in the amyloid fibrillogenesis process by interacting hydrophobically with the amino acid residues found in highly prone amyloid fibril forming region of HEWL as explicated by molecular docking results. The results recommend NA as a probable neuroprotective and promising inhibitor for the therapeutic advancement prospective against amyloid related diseases.
Research Interests: Biochemistry, Chemistry, Kinetics, Fluorescence Microscopy, Medicine, and 15 moreAmyloid, Humans, Lysozyme, Light, Hydrogen Bonding, Protein Conformation, Thiazoles, Fibrillogenesis, Protein Binding, Nephelometry and Turbidimetry, Amyloidosis, Biochemistry and cell biology, Minimum inhibitory concentration, Protein aggregates, and Minimum Inhibitory Concentration
F-box protein FBXW8 is known to interact with scaffolding protein Cullin1 and Cullin7 to form SCF (SKP1, Cullin and F-box protein) complex. However, detail understanding about the importance of both Cullins for SCF-FBXW8 complex formation... more
F-box protein FBXW8 is known to interact with scaffolding protein Cullin1 and Cullin7 to form SCF (SKP1, Cullin and F-box protein) complex. However, detail understanding about the importance of both Cullins for SCF-FBXW8 complex formation as well as its ubiquitin ligase activity remains elusive. Here, we show that, through in vitro and in vivo studies, Cullin1 and Cullin7 increase each other's binding to FBXW8 synergistically. Interestingly, absence of either Cullin results in abrogation of binding of other Cullin to FBXW8. Binding of SKP1 to FBXW8 also increases in the presence of both the Cullins. Thus, SKP1, Cullin1 and Cullin7 are essential to form Cullin1-SKP1-FBXW8-Cullin7 functional ubiquitin ligase complex. Further, using computational, mutational and biochemical analysis, we found that Cullin1 binds to N-terminus of FBXW8 through SKP1 while Cullin7 associates with C-terminus of FBXW8 to form Cullin1-SKP1-FBXW8-Cullin7 functional complex in a cooperative manner. Results showed that Cullin1-SKP1-FBXW8-Cullin7 complex plays a key role in maintaining the basal level expression of β-TrCP1. Moreover, Cullin1-SKP1-FBXW8-Cullin7 complex promotes cell migration by activating β-catenin via directing proteasomal degradation of β-TrCP1. Overall, our study reveals the intriguing molecular mechanism of assembly of SKP1, Cullin1, Cullin7 and FBXW7 to form Cullin1-SKP1-FBXW8-Cullin7 functional complex that control the function of β-TrCP1.
Research Interests:
Research Interests:
Research Interests: Chemistry, Biology, Cell Biology, DNA damage, Apoptosis, and 3 moreUbiquitin, Proteasome, and Ubiquitin ligase
Research Interests:
Research Interests:
Research Interests:
Although the cure of amyloid related neurodegenerative diseases, non-neuropathic amyloidogenic diseases and non-neuropathic systemic amyloidosis are appealing energetic research attempts, beneficial medication is still to be discovered.... more
Although the cure of amyloid related neurodegenerative diseases, non-neuropathic amyloidogenic diseases and non-neuropathic systemic amyloidosis are appealing energetic research attempts, beneficial medication is still to be discovered. There is a need to explore intensely stable therapeutic compounds, potent enough to restrict, disrupt or wipe out such toxic aggregates. We had performed a comprehensive biophysical, computational and cell based assay, that shows Nordihydroguaiaretic acid (NA) not only significantly inhibits heat induced hen egg white lysozyme (HEWL) fibrillation but also disaggregates preformed HEWL fibrils and reduces the cytoxicity of amyloid fibrils as well as disaggregated fibrillar species. The inhibitory potency of NA was determined by an IC50 of 26.3 μM. NA was also found to effectively inhibit human lysozyme (HL) fibrillation. NA interferes in the amyloid fibrillogenesis process by interacting hydrophobically with the amino acid residues found in highly pron...
Research Interests: Biochemistry, Chemistry, Kinetics, Fluorescence Microscopy, Medicine, and 14 moreAmyloid, Humans, Lysozyme, Light, Hydrogen Bonding, Protein Conformation, Thiazoles, Fibrillogenesis, Protein Binding, Nephelometry and Turbidimetry, Amyloidosis, Biochemistry and cell biology, Minimum inhibitory concentration, and Protein aggregates
An efficient and versatile strategy towards apio and homologated apio pyrimidines has been described via one pot oxidative cleavage and acetylation using Pb(OAc)4.
Research Interests:
SummaryApoptosis inhibitor 5 (Api5) is an inhibitor of apoptosis, which is found to be upregulated in several cancers and promotes invasion as well as metastasis. Over-expression of Api5 is positively co-related with poor survival of... more
SummaryApoptosis inhibitor 5 (Api5) is an inhibitor of apoptosis, which is found to be upregulated in several cancers and promotes invasion as well as metastasis. Over-expression of Api5 is positively co-related with poor survival of cancers and inhibition of DNA damage induced apoptosis in cancerous cells. Acetylation at lysine 251 (K251) on Api5 facilitates the stability of the protein and thus functionally provides resistance to cancer cells against chemotherapeutic or anti-cancerous agents. However, the regulation of Api5 upon DNA damage is not yet known. In this study, we demonstrate that Api5 undergoes degradation following DNA damage via the ubiquitin-proteasome system. Upon DNA damage, ATR was observed to phosphorylate Api5 at serine 138 which led to the cytoplasmic localisation of Api5. The E3-ubiquitin ligase, SCF-FBXW2 ubiquitinates Api5 leading to its proteasomal degradation.
Research Interests: Chemistry, Biology, Cell Biology, DNA damage, Apoptosis, and 3 moreUbiquitin, Proteasome, and Ubiquitin ligase
Multiple myeloma (MM) is a plasma cell‑associated cancer and accounts for 13% of all hematological malignancies, worldwide. MM still remains an incurable plasma cell malignancy with a poor prognosis due to a lack of suitable markers.... more
Multiple myeloma (MM) is a plasma cell‑associated cancer and accounts for 13% of all hematological malignancies, worldwide. MM still remains an incurable plasma cell malignancy with a poor prognosis due to a lack of suitable markers. Therefore, discovering novel markers and targets for diagnosis and therapeutics of MM is essential. The present study aims to identify markers associated with MM malignancy using patient‑derived MM mononuclear cells (MNCs). Label‑free quantitative proteomics analysis revealed a total of 192 differentially regulated proteins, in which 79 proteins were upregulated and 113 proteins were found to be downregulated in MM MNCs as compared to non‑hematological malignant samples. The identified differentially expressed candidate proteins were analyzed using various bioinformatics tools, including Ingenuity Pathway Analysis (IPA), Protein Analysis THrough Evolutionary Relationships (PANTHER), Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) an...
Research Interests:
Research Interests:
Sequential alteration in the expression levels of cell cycle regulatory proteins is crucial for faithful cell cycle progression to maintain the cellular homeostasis. F‐box protein β‐TrCP1 is known to control the expression levels of... more
Sequential alteration in the expression levels of cell cycle regulatory proteins is crucial for faithful cell cycle progression to maintain the cellular homeostasis. F‐box protein β‐TrCP1 is known to control the expression levels of several important cell cycle regulatory proteins. However, how the function of β‐TrCP1 is regulated in spatiotemporal manner during cell cycle progression remains elusive. Here, we show that expression levels of β‐TrCP1 oscillate during cell cycle progression with a minimum level at the G1 and S phases of cell cycle. Using biochemical, flow cytometry, and immunofluorescence techniques, we found that oscillation of β‐TrCP1 expression is controlled by another F‐box protein FBXW8. FBXW8 directs the proteasomal degradation of β‐TrCP1 in MAPK pathway‐dependent manner. Interestingly, we found that the attenuation of β‐TrCP1 by FBXW8 is important for Cdc25A‐mediated cell cycle transition from G1 phase to S phase as well as DNA damage‐free progression of S phase. Overall, our study reveals the intriguing molecular mechanism and significance of maintenance of β‐TrCP1 levels during cell cycle progression by FBXW8‐mediated proteasomal degradation.
Research Interests:
Research Interests:
Research Interests:
In this study, one step hydrothermal synthetic strategy was adopted for preparing carbon dots (C. dots) from jeera (Cumin: Cuminum cyminum), a naturally abundant and cost effective carbon source. The physical, optical and surface... more
In this study, one step hydrothermal synthetic strategy was adopted for preparing carbon dots (C. dots) from jeera (Cumin: Cuminum cyminum), a naturally abundant and cost effective carbon source. The physical, optical and surface functional properties of C. dots were extensively studied by different techniques such as Transmission electron microscopy (TEM), Scanning electron microscopy (SEM), spectrophotometry, fluorescence spectroscopy, Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The obtained C. dots were highly water dispersible and photostable with a quantum yield of 5.33%. The antioxidant property of C. dots was investigated by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) assay. The C. dots were then capped with cystamine using 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) coupling chemistry to design a selective sensing system for chromium (VI) (Cr (VI)). The minimum detection limit of Cr (VI) was found to be 1.57 μM. Biocompatibility and low toxicity of C. dots obtained from jeera made it a potential tool for bioimaging application. The internalisation of C. dots by MCF-7 breast cancer cells and Multi Drug Resistant (MDR) pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa were proved by the bioimaging of respective cells.
Research Interests:
In view of the potent anticancer activity of the d‐arabino‐configured cytosine nucleoside (ara‐C), apioarabinofuranosyl pyrimidine nucleosides were designed and synthesized from d‐ribose as starting material. The synthetic strategy... more
In view of the potent anticancer activity of the d‐arabino‐configured cytosine nucleoside (ara‐C), apioarabinofuranosyl pyrimidine nucleosides were designed and synthesized from d‐ribose as starting material. The synthetic strategy signifies that tosylation followed by in situ cyclization, one‐pot controlled oxidative cleavage and acetylation by Pb(OAc)4, stereoselective nucleobase condensation, inversion of hydroxyl group and uracil group converted to cytosine as the key steps. Synthesized apioarabinofuranosyl pyrimidine nucleosides were tested using breast, colon, and ovarian cancer cell lines. However, only compound 19a, 19b, and 22b have a moderate growth‐suppressive effect against the luminal A breast cancer cell line MCF7.
Research Interests:
F-box protein 31 (FBXO31) is a reported putative tumor suppressor, and its inactivation due to loss of heterozygosity is associated with cancers of different origins. An emerging body of literature has documented FBXO31's role in... more
F-box protein 31 (FBXO31) is a reported putative tumor suppressor, and its inactivation due to loss of heterozygosity is associated with cancers of different origins. An emerging body of literature has documented FBXO31's role in preserving genome integrity following DNA damage and in the cell cycle. However, knowledge regarding the role of FBXO31 during normal cell-cycle progression is restricted to its functions during the G2/M phase. Interestingly, FBXO31 levels remain high even during the early G1 phase, a crucial stage for preparing the cells for DNA replication. Therefore, we sought to investigate the functions of FBXO31 during the G1 phase of the cell cycle. Here, using flow cytometric, biochemical, and immunofluorescence techniques, we show that FBXO31 is essential for maintaining optimum expression of the cell-cycle protein cyclin A for efficient cell-cycle progression. Stable FBXO31 knockdown led to atypical accumulation of cyclin A during the G1 phase, driving premature DNA replication and compromised loading of the minichromosome maintenance complex, resulting in replication from fewer origins and DNA double-strand breaks. Because of these inherent defects in replication, FBXO31-knockdown cells were hypersensitive to replication stress-inducing agents and displayed pronounced genomic instability. Upon entering mitosis, the cells defective in DNA replication exhibited a delay in the prometaphase–to–metaphase transition and anaphase defects such as lagging and bridging chromosomes. In conclusion, our findings establish that FBXO31 plays a pivotal role in preserving genomic integrity by maintaining low cyclin A levels during the G1 phase for faithful genome duplication and segregation.
Research Interests:
Research Interests:
Cyclin F protein, also known as FBXO1, is the largest among all cyclins and oscillates in the cell cycle like other cyclins. Apart from being a G2/M cyclin, cyclin F functions as the substrate-binding subunit of SCF(cyclin F) E3 ubiquitin... more
Cyclin F protein, also known as FBXO1, is the largest among all cyclins and oscillates in the cell cycle like other cyclins. Apart from being a G2/M cyclin, cyclin F functions as the substrate-binding subunit of SCF(cyclin F) E3 ubiquitin ligase. In a gene expression analysis performed to identify novel gene modulations associated with cell cycle dysregulation during HIV-1 infection in CD4(+) T cells, we observed down-regulation of the cyclin F gene (CCNF). Later, using gene overexpression and knockdown studies, we identified cyclin F as negatively influencing HIV-1 viral infectivity without any significant impact on virus production. Subsequently, we found that cyclin F negatively regulates the expression of viral protein Vif (viral infectivity factor) at the protein level. We also identified a novel host-pathogen interaction between cyclin F and Vif protein in T cells during HIV-1 infection. Mutational analysis of a cyclin F-specific amino acid motif in the C-terminal region of Vi...
Research Interests:
Series of novel truncated carbocyclic nucleoside analogues have been synthesized from the versatile starting material D-ribose and their anticancer activities have been evaluated. The nucleoside analogues induced cytotoxicity in breast... more
Series of novel truncated carbocyclic nucleoside analogues have been synthesized from the versatile starting material D-ribose and their anticancer activities have been evaluated. The nucleoside analogues induced cytotoxicity in breast and ovarian cancer cell lines. These compounds are less cytotoxic to normal kidney cell line (HEK 293) as compared to the cancer cells. Among the synthesized compounds, 1b and 1d showed the better cytotoxic effect with IC50 44 and 54 μM, in MCF7 cells, respectively. These compounds inactivate the important signaling kinases AKT and mTOR and thereby induce autophagy. Collectively our observation suggests that compound 1b and 1d inhibit the cancer cell proliferation through induction of autophagy mode of cell death.