Mehdi Mollapour (born June 14, 1973) is a British-American Biochemist and Cancer Biologist. He is a Professor, Vice Chair for Translational Research and Director of Renal Cancer Biology Program for the Department of Urology, and Adjunct Professor at the Department of Biochemistry and Molecular Biology at SUNY Upstate Medical University.[1][2]
Mollapour completed his postdoctoral research at the University of Sheffield and in 2006 he received the Federation of European Societies (FEBS) fellowship.[1]
He joined the laboratory of Dr Len Neckers in Urological Oncology Branch, (Chief Dr. W. Marston Linehan), at the National Cancer Institute as a research fellow in 2007.[2]
In 2013 he joined the Department of Urology at the Upstate Medical University as an Assistant Professor. He became the Director of the Kidney Cancer Program within the same department in 2015.[1]
In 2018 he became the Professor of Urology and Adjunct Professor of Biochemistry and Molecular Biology at SUNY Upstate Medical University. He was also named the Vice Chair for Translational Research for the Department of Urology in the same year.[2] In 2023, Mollapour was elected the president-elect for the Cell Stress Society International; his term at president will begin in 2025.[3] Mollapour’s h-index is 45, based on 7,751 citations.[4]
Research
Molecular Chaperones
Mollapour is widely recognized for his research on post-translation regulation of the molecular chaperone Heat shock protein-90 (Hsp90)[5][6] and co-chaperones in cancer. His work demonstrated how reversible biochemical reactions can become directional and ordered, and in general, how a house-keeping machine (Hsp90) can be modulated through signaling inputs. Mollapour’s finding on post-translational modifications of the Hsp90 chaperone machinery has also explained the reasons for tumors sensitivity and selectivity towards the Hsp90 inhibitors. [7][6]
Tuberous Sclerosis Complex and Birt–Hogg–Dubé syndrome (BHD)
Mollapour’s laboratory has discovered the tumor suppressor TSC1 and FNIPs function as the new co-chaperones of Hsp90.[8][9][10][11] These two proteins are involved in Tuberous Sclerosis Complex and Birt–Hogg–Dubé syndrome (BHD) syndromes respectively. His research has identified a cross-talk between these two co-chaperones and demonstrated interconnectivity and compensatory mechanisms between the BHD and TSC pathways.[6]
Kidney Cancer
Mutations and loss of function of the Von Hippel-Lindau (VHL) tumor suppressor gene play a causal role in the pathogenesis of clear cell renal carcinomas (ccRCC), a pathological subtype that accounts for the majority kidney cancer each year. Mollapour work has shown that VHL ubiquitinates protein phosphatase-5 (PP5) for proteasomal degradation in a hypoxia- and prolyl-hydroxylation-independent manner. VHL-deficient ccRCC cell lines and patient tumors exhibit elevated PP5 levels. Downregulation of PP5 causes activation of the extrinsic apoptotic pathway in ccRCC cells, suggesting a prosurvival role for PP5 in kidney cancer.[12][13]
Aerobic glycolysis in cancer cells, also known as the “Warburg effect”, is driven by hyperactivity of lactate dehydrogenase-A (LDHA). Mollapour’s team has identified the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. Their work has provided a new paradigm for the regulation of glycolysis. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Mollapour’s lab has shown that treatment of these cancer cells with a decapeptide derived from the FLCN loop region caused cell death, therefore providing a new avenue for targeted therapy in these cancers.[14][15]
Recognition
2023 President-elect Cell Stress Society International[16]
2019 Fellow of Cell Stress Society International[17]
2017 Society for Basic Urological Research Young Investigator[18][19]
2017 American Urological Association Research Scholar[19]
2013 Early Career Award, Cell Stress Society International[20]
2011 2011 Lasker~Bloomberg Public Service Award, as member of the recipient team at The Clinical Center of the National Institutes of Health [21]
2010 Intramural National Cancer Institute (NCI) Fellow and Young Investigator of the Year[2]
Dunn DM, Woodford MR, Truman AW, Jensen SM, Schulman J, Caza T, Remillard TC, Loiselle D, Wolfgeher D, Blagg BS, Franco L, Haystead TA, Daturpalli S, Mayer MP, Trepel JB, Morgan RM, Prodromou C, Kron SJ, Panaretou B, Stetler-Stevenson WG, Landas SK, Neckers L, Bratslavsky G, Bourboulia D, Mollapour M. c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells. Cell reports. 2015;12(6):1006-18. doi: 10.1016/j.celrep.2015.07.004. PubMed PMID26235616.
Mollapour M, Bourboulia D, Beebe K, Woodford MR, Polier S, Hoang A, Chelluri R, Li Y, Guo A, Lee MJ, Fotooh-Abadi E, Khan S, Prince T, Miyajima N, Yoshida S, Tsutsumi S, Xu W, Panaretou B, Stetler-Stevenson WG, Bratslavsky G, Trepel JB, Prodromou C, Neckers L. Asymmetric Hsp90 N Domain SUMOylation Recruits Aha1 and ATP-Competitive Inhibitors. Mol Cell. 2014;53(2):317-29. doi: 10.1016/j.molcel.2013.12.007. PubMed PMID24462205.
Mollapour is married to Dimitra Bourboulia, PhD, Associate Professor, Assistant Dean for Undergraduate and Graduate Medical Education Research, and Director for the Office of Research for Medical Students, at SUNY Upstate Medical University.[22][23]
Related Research Articles
In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assist large proteins in proper protein folding during or after synthesis, and after partial denaturation. Chaperones are also involved in the translocation of proteins for proteolysis.
Hsp90 is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs.
Heat shock protein 27 (Hsp27) also known as heat shock protein beta-1 (HSPB1) is a protein that in humans is encoded by the HSPB1 gene.
Tuberous sclerosis 1 (TSC1), also known as hamartin, is a protein that in humans is encoded by the TSC1 gene.
The tumor suppressor gene FLCN encodes the protein folliculin, also known as Birt–Hogg–Dubé syndrome protein, which functions as an inhibitor of Lactate Dehydrogenase-A and a regulator of the Warburg effect. Folliculin (FLCN) is also associated with Birt–Hogg–Dubé syndrome, which is an autosomal dominant inherited cancer syndrome in which affected individuals are at risk for the development of benign cutaneous tumors (folliculomas), pulmonary cysts, and kidney tumors.
Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the HSP90AA1 gene.
Human gene HSPA1B is an intron-less gene which encodes for the heat shock protein HSP70-2, a member of the Hsp70 family of proteins. The gene is located in the major histocompatibility complex, on the short arm of chromosome 6, in a cluster with two paralogous genes, HSPA1A and HSPA1L. HSPA1A and HSPA1B produce nearly identical proteins because the few differences in their DNA sequences are almost exclusively synonymous substitutions or in the three prime untranslated region, heat shock 70kDa protein 1A, from HSPA1A, and heat shock 70kDa protein 1B, from HSPA1B. A third, more modified paralog to these genes exists in the same region, HSPA1L, which shares a 90% homology with the other two.
Tuberous Sclerosis Complex 2 (TSC2), also known as Tuberin, is a protein that in humans is encoded by the TSC2 gene.
Heat shock protein 90kDa beta member 1 (HSP90B1), known also as endoplasmin, gp96, grp94, or ERp99, is a chaperone protein that in humans is encoded by the HSP90B1 gene.
Heat shock protein HSP 90-beta also called HSP90beta is a protein that in humans is encoded by the HSP90AB1 gene.
DnaJ homolog subfamily A member 3, mitochondrial, also known as Tumorous imaginal disc 1 (TID1), is a protein that in humans is encoded by the DNAJA3 gene on chromosome 16. This protein belongs to the DNAJ/Hsp40 protein family, which is known for binding and activating Hsp70 chaperone proteins to perform protein folding, degradation, and complex assembly. As a mitochondrial protein, it is involved in maintaining membrane potential and mitochondrial DNA (mtDNA) integrity, as well as cellular processes such as cell movement, growth, and death. Furthermore, it is associated with a broad range of diseases, including neurodegenerative diseases, inflammatory diseases, and cancers.
DnaJ homolog subfamily B member 1 is a protein that in humans is encoded by the DNAJB1 gene.
Hsc70-interacting protein also known as suppression of tumorigenicity 13 (ST13) is a protein that in humans is encoded by the ST13 gene.
Activator of 90 kDa heat shock protein ATPase homolog 1 is an enzyme that in humans is encoded by the AHSA1 gene.
AHSA2 also known as AHA1, activator of heat shock 90kDa protein ATPase homolog 2 (yeast) is a human gene which encodes a protein which acts as co-chaperone of Hsp90. AHSA2 and the related AHSA1 belongs to the AHA family of stress-regulated proteins that bind directly to Hsp90 and are required for Hsp90-dependent activation of client proteins.
The GHKL domain is an evolutionary conserved protein domain. It is an ATPase domain found in several ATP-binding proteins such as histidine kinase, DNA gyrase B, topoisomerases, heat shock protein HSP90, phytochrome-like ATPases and DNA mismatch repair proteins.
An Hsp90 inhibitor is a substance that inhibits that activity of the Hsp90 heat shock protein. Since Hsp90 stabilizes a variety of proteins required for survival of cancer cells, these substances may have therapeutic benefit in the treatment of various types of malignancies. Furthermore, a number of Hsp90 inhibitors are currently undergoing clinical trials for a variety of cancers. Hsp90 inhibitors include the natural products geldanamycin and radicicol as well as semisynthetic derivatives 17-N-Allylamino-17-demethoxygeldanamycin (17AAG).
Laurence Harris Pearl FRS FMedSci is a British biochemist and structural biologist who is currently Professor of Structural Biology in the Genome Damage and Stability Centre and was Head of the School of Life Sciences at the University of Sussex.
The chaperone code refers to post-translational modifications of molecular chaperones that control protein folding. Whilst the genetic code specifies how DNA makes proteins, and the histone code regulates histone-DNA interactions, the chaperone code controls how proteins are folded to produce a functional proteome.
Folliculin-interacting protein 1 (FNIP1) functions as a co-chaperone which inhibits the ATPase activity of the chaperone Hsp90 and decelerates its chaperone cycle. FNIP1 acts as a scaffold to load FLCN onto Hsp90. FNIP1 is also involved in chaperoning of both kinase and non-kinase clients.
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