Research interests:

Major objectives in the lab include

-Finding small molecule modulators of HSF1 from natural sources and study their mode of actions to assess their cellular toxicity/potential therapeutic efficacy. 

-Study control of HSF1 function in cells by biochemical approaches. We are interested to know the factors that collaborate with HSF1 under different cellular stressful environments.

-Finding small molecules from natural sources that would kill cancer cells of different organ origins with high specificity, and study their mode of actions to assess toxicity associated with using these molecules.  

Contact:

Address: Division of Molecular Medicine
Centenary Campus
Bose Institute
P-1/12 C.I.T. Scheme VII-M
Kolkata - 700054, India
E-Mail: mahadeb[at]jcbose.ac.in
Phone: +91-33-25693256

Research:

A normal cell can sense if a protein is misfolded or aggregated and take appropriate action to stay healthy. A healthy cell under this circumstance activates heat shock response (HSR), also called proteotoxic stress response (PSR) to upregulate the expression of genes encoding protein chaperones to refold the protein back to its native conformation. In case it is not appropriate- the protein is degraded by activation of processes such as proteasome and or autophagy pathway(s) to maintain a healthy cellular environment. The HSR dies down to inactive state as usual as the stress is neutralized or removed. A central regulator of HSR is the heat shock factor 1 (HSF1), a transcription activator. HSR upregulation is marked by activated state of cellular HSF1 protein. It has been shown by independent laboratories that cells in transformed as well as neurodegenerative states lose standard control over their HSF1 function. For example, cancer cells maintain a constitutively activated state of HSF1 and downregulation of HSF1 was shown to sensitize cancer cells. On the other hand the cells with a neurodegenerative condition as occur in diseases like Parkinson’s disease, being unable to sense the accumulation of protein aggregate, fail to upregulate HSF1 function. These cells die due to toxicity caused by the protein aggregate it accumulates. It has been found by independent investigators that forced upregulation of HSF1 or its target protein chaperone ameliorates the protein misfolding associated toxicity in animal model. Thus far however no specific small molecule activator/inhibitor of HSF1 has reached the clinic. To this end we have already isolated a compound (azadiradione) that activates HSF1 by direct interaction with the protein. This is the only compound thus far reported that activates HSF1 by interact interaction. We- in another project- are investigating how PSR links with cellular inflammation- a critical mediator of cellular transformation- have unearthed a unique mechanism. Projects are running well in the lab to isolate small molecules anticancer agents from natural sources based on studies with cell and animal models.  

Publications:

1. Safina A, Cheney P, Pal M, Brodsky L, Ivanov A, Kirsanov K, Lesovaya E, Naberezhnov D, Nesher E, Koman I, Wang D, Wang J, Yakubovskaya M, Winkler D, Gurova K (2017) FACT is a sensor of DNA torsional stress in eukaryotic cells, Nucleic Acid Research, Jan 12, 2017

 

2. Hazra, J., Mukherjee, P., Ali, A., and Pal, M. (2017) Engagement of Components of DNA-Break Repair Complex and NFκB in Hsp70A1A Transcription Upregulation by Heat Shock. PLOS ONE Jan 18;12(1):e0168165

 

3.Nelson, VK., Ali, A., Dutta., N., Ghosh, S., Jana, M., Ganguli, A., Komaro, A., Paul, S., Dwivedi, V., Chatterjee, S.,Jana, N., Lakhotia, SC., Chakrabarti, GC., Misra, AK., Mandal, SC., Pal, M. (2016) Azadiradione ameliorates polyglutamine expansion disease in Drosophila by potentiating DNA binding activity of heat shock factor 1, Oncotarget, vol 7, no 48, p 78281

 

4.Ghosh, N., Ali, A., Das, S., Mandal, S.C., and Pal, M. (2016) Chronic Inflammatory Diseases: Progress and Prospect with Herbal Medicine. Curr Pharm Des. 22(2): 247-64

 

5. Dhar G, Chakravarty D, Hazra J, Dhar J, Poddar A, Pal M, Chakrabarti P, Surolia A, Bhattacharyya B (2015) Actin-curcumin interaction: insights into the mechanism of actin polymerization inhibition.

Biochemistry 54:1132-43.  

 

 

6. Pal S., Bhattacharjee B., Mandal N C, Mandal S C. and Pal M. (2014) Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 antagonism. J Inflamm (Lond). 2014 Aug 9;11:23.

 

7. Leonova KI, Brodsky L, Lipchick B, Pal M, Novototskaya L, Chenchik AA, Sen GC, Komarova EA, Gudkov AV (2013) p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs. Proc Natle Acad Sci (USA), 2013 2;110-89-98.

 

8. Gasparian AV, Burkhart CA, Purmal AA, Brodsky L, Pal M, Saranadasa M, Bosykh DA, Commane M, Guryanova OA, Pal S, Safina A, Sviridov S, Koman IE, Veith J, Komar AA, Gudkov AV, and Gurova KV 2011. Curaxins: anticancer compounds that simultaneously suppress NF-κB and activate p53 by targeting FACT. Sci Transl Med. 3, 95ra74.

 

9. Újvári A, Pal M, and Donal L (2011) The functions of TFIIF during initiation and transcript elongation are differentially affected by phosphorylation by casein kinase 2. J Biol Chem 286, 23160-7.

 

10. Čabart P,  Újvári A, Pal M and Luse D. (2011) TFIIF is not required for initiation by RNA polymerase II but it is essential to stabilize TFIIB in early transcription complexes, Proc  Natle  Acad Sci (USA), Sep 20;108(38):15786-91.

 

11. Pal M, Ponticelli A S,  and Luse D (2005)The role of the transcription bubble and TFIIB in promoter clearance by RNA polymerase II. Molecular Cell, 19, 101-110. 

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