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Pharmacology & Systems Physiology 

Photo of  Maria Czyzyk-Krzeska, MD, PhD

Maria Czyzyk-Krzeska, MD, PhD

Professor

Education/Credentials
  • Medical Degree: Warsaw Medical School
  • PhD Degree: Warsaw Medical School

Research/Clinical Interests

For the last 15 years, my laboratory has conducted mechanistic studies of signaling pathways and regulatory molecular mechanisms that regulate cancer cell survival and tumor growth in renal cancer. In particular, we have focused our interests on the von Hippel-Lindau tumor suppressor (VHL), lost in majority of renal cancers, and autophagy. Renal cancer accounts for 2-3% of adult malignancies in the USA with clear cell renal carcinoma (ccRCC) as the main histological type. Current treatments include anti-angiogenic agents based on the understanding that the loss of VHL results in activation of HIF and VEGF. However, these treatments have a limited impact on survival. Thus, it is critical to identify novel pathways as specific targets for the development of new therapies. Autophagy is a tightly regulated homeostatic process which allows cells to eliminate defective structures and to recycle nutrients. In several cancers, including ccRCC, basic autophagy is elevated and necessary for tumor growth. Autophagy is also induced by inhibitors of angiogenesis, mTOR pathway or proteasome, leading to resistance to treatments. We established that in ccRCC, a specific LC3B-mediated autophagic program is activated by the loss of VHL, and LC3B activity contributes to tumor growth. Another autophagic program, mediated by LC3B paralog, LC3C, is stimulated by VHL and has tumor suppressing activity. Most recently we identified that two products of TRPM3 gene, microRNA 204 (miR-204) and transient receptor potential channel, TRPM3, have opposite roles in ccRCC. Mir-204 is induced by VHL and acts as a tumor suppressor inhibiting oncogenic autophagy, while TRPM3 acts as an oncogene and promotes oncogenic autophagy.

Contact Information
  • Vontz Center for Molecular Studies
  • 3125 Eden Avenue
  • ML 0521
  • Cincinnati, Ohio 45267
  • Office 513-558-1957
  • Email maria.czyzyk-krzeska@uc.edu

Peer Reviewed Publications

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Zhang, Yuqian; Rana, Ankit; Stratton, Yiwen; Czyzyk-Krzeska, Maria F; Esfandiari, Leyla 2017. Sequence-Specific Detection of MicroRNAs Related to Clear Cell Renal Cell Carcinoma at fM Concentration by an Electroosmotically Driven Nanopore-Based Device. Analytical chemistry, 89 17, 9201-9208

Klionsky DJ, Czyzyk-Krzeska MF, et al. 2016. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) Autophagy, 12 , 1-222

Cost, Nicolas G; Czyzyk-Krzeska, Maria F 2015. Regulation of autophagy by two products of one gene: TRPM3 and miR-204. Molecular & cellular oncology, 2 4, e1002712

N.G. Cost, M.F. Czyzyk-Krzeska 2015. Regulation of autophagy by two products of one gene: TRPM3 and miR-204 Molecular and Cellular Oncology Molecular and Cellular Oncology, 2 4,

Czyzyk-Krzeska, M F; Zhang, X 2014. MiR-155 at the heart of oncogenic pathways Oncogene, 33 6, 677-8

Hall, Daniel P; Cost, Nicholas G; Hegde, Shailaja; Kellner, Emily; Mikhaylova, Olga; Stratton, Yiwen; Ehmer, Birgit; Abplanalp, William A; Pandey, Raghav; Biesiada, Jacek; Harteneck, Christian; Plas, David R; Meller, Jarek; Czyzyk-Krzeska, Maria F 2014. TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma. Cancer cell, 26 5, 738-53

Bastola, Prabhat; Stratton, Yiwen; Kellner, Emily; Mikhaylova, Olga; Yi, Ying; Sartor, Maureen A; Medvedovic, Mario; Biesiada, Jacek; Meller, Jarek; Czyzyk-Krzeska, Maria F 2013. Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy. PloS one, 8 7, e70030

Czyzyk-Krzeska, Maria F; McCormack, Francis X 2013. Birt-Hogg-Dubé syndrome. Familial cancer, 12 3, 355-6

Kawedia, Jitesh D; Yang, Fan; Sartor, Maureen A; Gozal, David; Czyzyk-Krzeska, Maria; Menon, Anil G 2013. Hypoxia and hypoxia mimetics decrease aquaporin 5 (AQP5) expression through both hypoxia inducible factor-1alpha and proteasome-mediated pathways. PloS one, 8 3, e57541

Czyzyk-Krzeska, Maria F; Meller, Jarek; Plas, David R 2012. Not all autophagy is equal. Autophagy, 8 7, 1155-6

Mikhaylova, Olga; Stratton, Yiwen; Hall, Daniel; Kellner, Emily; Ehmer, Birgit; Drew, Angela F; Gallo, Catherine A; Plas, DR; Biesiada, Jacek; Meller, Jarek; Czyzyk-Krzeska, Maria F 2012. VHL-regulated MiR-204 suppresses tumor growth through inhibition of LC3B-mediated autophagy in renal clear cell carcinoma. Cancer cell, 21 4, 532-46

Yi, Ying; Mikhaylova, Olga; Mamedova, Aygun; Bastola, Prabhat; Biesiada, Jacek; Alshaikh, Enas; Levin, Linda; Sheridan, Rachel M; Meller, Jarek; Czyzyk-Krzeska, Maria F 2010. von Hippel-Lindau-dependent patterns of RNA polymerase II hydroxylation in human renal clear cell carcinomas. Clinical cancer research : an official journal of the American Association for Cancer Research, 16 21, 5142-52

Haffey, Wendy D; Mikhaylova, Olga; Meller, Jarek; Yi, Ying; Greis, Kenneth D; Czyzyk-Krzeska, Maria F 2009. iTRAQ proteomic identification of pVHL-dependent and -independent targets of Egln1 prolyl hydroxylase knockdown in renal carcinoma cells. Advances in enzyme regulation, 49 1, 121-32

Ignacak, M L; Harbaugh, S V; Dayyat, E; Row, B W; Gozal, D; Czyzyk-Krzeska, M F 2009. Intermittent hypoxia regulates RNA polymerase II in hippocampus and prefrontal cortex. Neuroscience, 158 4, 1436-45

Siroky, Brian J; Czyzyk-Krzeska, Maria F; Bissler, John J 2009. Renal involvement in tuberous sclerosis complex and von Hippel-Lindau disease: shared disease mechanisms? Nature clinical practice. Nephrology, 5 3, 143-56

Mikhaylova, Olga; Ignacak, Monika L; Barankiewicz, Teresa J; Harbaugh, Svetlana V; Yi, Ying; Maxwell, Patrick H; Schneider, Martin; Van Geyte, Katie; Carmeliet, Peter; Revelo, Monica P; Wyder, Michael; Greis, Kenneth D; Meller, Jarek; Czyzyk-Krzeska, Maria F 2008. The von Hippel-Lindau tumor suppressor protein and Egl-9-Type proline hydroxylases regulate the large subunit of RNA polymerase II in response to oxidative stress. Molecular and cellular biology, 28 8, 2701-17

Hui, Anna S; Bauer, Amy L; Striet, Justin B; Schnell, Phillip O; Czyzyk-Krzeska, Maria F 2006. Calcium signaling stimulates translation of HIF-alpha during hypoxia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 20 3, 466-75

Gozal, Evelyne; Shah, Zahoor A; Pequignot, Jean-Marc; Pequignot, Jacqueline; Sachleben, Leroy R; Czyzyk-Krzeska, Maria F; Li, Richard C; Guo, Shang-Z; Gozal, David 2005. Tyrosine hydroxylase expression and activity in the rat brain: differential regulation after long-term intermittent or sustained hypoxia. Journal of applied physiology (Bethesda, Md. : 1985), 99 2, 642-9

Zakrzewska, Adriana; Schnell, Phillip O; Striet, Justin B; Hui, Anna; Robbins, Jennifer R; Petrovic, Milan; Conforti, Laura; Gozal, David; Wathelet, Marc G; Czyzyk-Krzeska, Maria F 2005. Hypoxia-activated metabolic pathway stimulates phosphorylation of p300 and CBP in oxygen-sensitive cells. Journal of neurochemistry, 94 5, 1288-96

Czyzyk-Krzeska, Maria F; Meller, Jaroslaw 2004. von Hippel-Lindau tumor suppressor: not only HIF's executioner. Trends in molecular medicine, 10 4, 146-9

Hui, Anna S; Striet, Justin B; Gudelsky, Gary; Soukhova, Galia K; Gozal, Evelyne; Beitner-Johnson, Dana; Guo, Shang-Z; Sachleben, Leroy R; Haycock, John W; Gozal, David; Czyzyk-Krzeska, Maria F 2003. Regulation of catecholamines by sustained and intermittent hypoxia in neuroendocrine cells and sympathetic neurons. Hypertension, 42 6, 1130-6

Kuznetsova, Anna V; Meller, Jaroslaw; Schnell, Phillip O; Nash, James A; Ignacak, Monika L; Sanchez, Yolanda; Conaway, Joan W; Conaway, Ronald C; Czyzyk-Krzeska, Maria F 2003. von Hippel-Lindau protein binds hyperphosphorylated large subunit of RNA polymerase II through a proline hydroxylation motif and targets it for ubiquitination. Proceedings of the National Academy of Sciences of the United States of America, 100 5, 2706-11

Schnell, Phillip O; Ignacak, Monika L; Bauer, Amy L; Striet, Justin B; Paulding, Waltke R; Czyzyk-Krzeska, Maria F 2003. Regulation of tyrosine hydroxylase promoter activity by the von Hippel-Lindau tumor suppressor protein and hypoxia-inducible transcription factors. Journal of neurochemistry, 85 2, 483-91

Akeno, Nagako; Robins, Jared; Zhang, Mei; Czyzyk-Krzeska, Maria F; Clemens, Thomas L 2002. Induction of vascular endothelial growth factor by IGF-I in osteoblast-like cells is mediated by the PI3K signaling pathway through the hypoxia-inducible factor-2alpha. Endocrinology, 143 2, 420-5

Bauer, Amy L; Paulding, Waltke R; Striet, Justin B; Schnell, Phillip O; Czyzyk-Krzeska, Maria F 2002. Endogenous von Hippel-Lindau tumor suppressor protein regulates catecholaminergic phenotype in PC12 cells. Cancer research, 62 6, 1682-7

Paulding, Waltke R; Schnell, Phillip O; Bauer, Amy L; Striet, Justin B; Nash, James A; Kuznetsova, Anna V; Czyzyk-Krzeska, Maria F 2002. Regulation of gene expression for neurotransmitters during adaptation to hypoxia in oxygen-sensitive neuroendocrine cells. Microscopy research and technique, 59 3, 178-87

Yeap, Bu B; Voon, Dominic C; Vivian, Julian P; McCulloch, Ross K; Thomson, Andrew M; Giles, Keith M; Czyzyk-Krzeska, Maria F; Furneaux, Henry; Wilce, Matthew C J; Wilce, Jackie A; Leedman, Peter J 2002. Novel binding of HuR and poly(C)-binding protein to a conserved UC-rich motif within the 3'-untranslated region of the androgen receptor messenger RNA. The Journal of biological chemistry, 277 30, 27183-92

Akeno, N; Czyzyk-Krzeska, M F; Gross, T S; Clemens, T L 2001. Hypoxia induces vascular endothelial growth factor gene transcription in human osteoblast-like cells through the hypoxia-inducible factor-2alpha. Endocrinology, 142 2, 959-62

Alterio, J; Mallet, J; Biguet, N F 2001. Multiple complexes involved in tyrosine hydroxylase mRNA stability in rat adrenal medulla, after reserpine stimulation. Molecular and cellular neurosciences, 17 1, 179-89

Kamura, T; Sato, S; Iwai, K; Czyzyk-Krzeska, M; Conaway, R C; Conaway, J W 2000. Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proceedings of the National Academy of Sciences of the United States of America, 97 19, 10430-5

Paulding, W R; Czyzyk-Krzeska, M F 2000. Hypoxia-induced regulation of mRNA stability. Advances in experimental medicine and biology, 475 , 111-21

Czyzyk-Krzeska, M F; Bendixen, A C 1999. Identification of the poly(C) binding protein in the complex associated with the 3' untranslated region of erythropoietin messenger RNA. Blood, 93 6, 2111-20

Kroll, S L; Paulding, W R; Schnell, P O; Barton, M C; Conaway, J W; Conaway, R C; Czyzyk-Krzeska, M F 1999. von Hippel-Lindau protein induces hypoxia-regulated arrest of tyrosine hydroxylase transcript elongation in pheochromocytoma cells. The Journal of biological chemistry, 274 42, 30109-14

Paulding, W R; Czyzyk-Krzeska, M F 1999. Regulation of tyrosine hydroxylase mRNA stability by protein-binding, pyrimidine-rich sequence in the 3'-untranslated region. The Journal of biological chemistry, 274 4, 2532-8

Kroll, S L; Czyzyk-Krzeska, M F 1998. Role of H2O2 and heme-containing O2 sensors in hypoxic regulation of tyrosine hydroxylase gene expression. The American journal of physiology, 274 1 Pt 1, C167-74

Czyzyk-Krzeska, M F 1997. Molecular aspects of oxygen sensing in physiological adaptation to hypoxia. Respiration physiology, 110 2-3, 99-111

Czyzyk-Krzeska, M F; Paulding, W R; Beresh, J E; Kroll, S L 1997. Post-transcriptional regulation of tyrosine hydroxylase gene expression by oxygen in PC12 cells. Kidney international, 51 2, 585-90

Czyzyk-Krzeska, M F; Beresh, J E 1996. Characterization of the hypoxia-inducible protein binding site within the pyrimidine-rich tract in the 3'-untranslated region of the tyrosine hydroxylase mRNA. The Journal of biological chemistry, 271 6, 3293-9

Czyzyk-Krzeska, M F; Paulding, W R; Lipski, J; Beresh, J E; Kroll, S L 1996. Regulation of tyrosine hydroxylase mRNA stability by oxygen in PC12 cells. Advances in experimental medicine and biology, 410 , 143-50

Zhu, W H; Conforti, L; Czyzyk-Krzeska, M F; Millhorn, D E 1996. Membrane depolarization in PC-12 cells during hypoxia is regulated by an O2-sensitive K+ current. The American journal of physiology, 271 2 Pt 1, C658-65

Chen, J; Dinger, B; Fidone, S J 1995. Second messenger regulation of tyrosine hydroxylase gene expression in rat carotid body. Biological signals, 4 5, 277-85

Norris, M L; Millhorn, D E 1995. Hypoxia-induced protein binding to O2-responsive sequences on the tyrosine hydroxylase gene. The Journal of biological chemistry, 270 40, 23774-9

Czyzyk-Krzeska, M F; Dominski, Z; Kole, R; Millhorn, D E 1994. Hypoxia stimulates binding of a cytoplasmic protein to a pyrimidine-rich sequence in the 3'-untranslated region of rat tyrosine hydroxylase mRNA. The Journal of biological chemistry, 269 13, 9940-5

Czyzyk-Krzeska, M F; Furnari, B A; Lawson, E E; Millhorn, D E 1994. Hypoxia increases rate of transcription and stability of tyrosine hydroxylase mRNA in pheochromocytoma (PC12) cells. The Journal of biological chemistry, 269 1, 760-4

Millhorn, D E; Czyzyk-Krzeska, M; Bayliss, D A; Lawson, E E 1993. Regulation of gene expression by hypoxia. Sleep, 16 8 Suppl, S44-8

Czyzyk-Krzeska, M F; Bayliss, D A; Lawson, E E; Millhorn, D E 1992. Regulation of tyrosine hydroxylase gene expression in the rat carotid body by hypoxia. Journal of neurochemistry, 58 4, 1538-46

Czyzyk-Krzeska, M F; Lawson, E E; Millhorn, D E 1992. Expression of D2 dopamine receptor mRNA in the arterial chemoreceptor afferent pathway. Journal of the autonomic nervous system, 41 1-2, 31-9

Czyzyk-Krzeska, M F; Bayliss, D A; Lawson, E E; Millhorn, D E 1991. Expression of messenger RNAs for peptides and tyrosine hydroxylase in primary sensory neurons that innervate arterial baroreceptors and chemoreceptors. Neuroscience letters, 129 1, 98-102

Czyzyk-Krzeska, M F; Bayliss, D A; Seroogy, K B; Millhorn, D E 1991. Gene expression for peptides in neurons of the petrosal and nodose ganglia in rat. Experimental brain research, 83 2, 411-8

Czyzyk-Krzeska, M F; Lawson, E E 1991. Synaptic events in ventral respiratory neurones during apnoea induced by laryngeal nerve stimulation in neonatal pig. The Journal of physiology, 436 , 131-47

Lawson, E E; Richter, D W; Czyzyk-Krzeska, M F; Bischoff, A; Rudesill, R C 1991. Respiratory neuronal activity during apnea and other breathing patterns induced by laryngeal stimulation. Journal of applied physiology (Bethesda, Md. : 1985), 70 6, 2742-9

Czyzyk-Krzeska, M F; Trzebski, A 1990. Respiratory-related discharge pattern of sympathetic nerve activity in the spontaneously hypertensive rat. The Journal of physiology, 426 , 355-68

Czyzyk-Krzeska, M F; Trzebski, A 1990. Respiratory modulation of the cutaneous somatosympathetic reflex in normotensive (WKY) and in spontaneously hypertensive rats (SHR): species and strain-dependent patterns. Acta neurobiologiae experimentalis, 50 3, 47-60

Krzeski, R; Trzebski, A; Czyzyk-Krzeska, M F 1990. Opposite excitatory and inhibitory effects of central administration of glucagon and of insulin upon the sympathetic cervical and adrenal nerve activities in the rat. Acta physiologica Polonica, 41 4-6, 115-21

Dean, J B; Czyzyk-Krzeska, M; Millhorn, D E 1989. Experimentally induced postinhibitory rebound in rat nucleus ambiguus is dependent on hyperpolarization parameters and membrane potential. Neuroscience research, 6 5, 487-93

Krzeski, R; Czyzyk-Krzeska, M F; Trzebski, A; Millhorn, D E 1989. Centrally administered glucagon stimulates sympathetic nerve activity in rat. Brain research, 504 2, 297-300

Millhorn, D E; Bayliss, D A; Erickson, J T; Gallman, E A; Szymeczek, C L; Czyzyk-Krzeska, M; Dean, J B 1989. Cellular and molecular mechanisms of chemical synaptic transmission. The American journal of physiology, 257 6 Pt 1, L289-310