Cellular Adaptation to Oxygen Seminar 4112019 By Noha

Cellular Adaptation to Oxygen Seminar 4/11/2019 By : Noha Elzeiny Mohammed Esawie

Outlines • • • Aim Background HIF (hypoxic inducible factor) Structure of HIF-1α Regulators and Genes affected Physiological and pathological impact

Aim • The Nobel Prize in Medicine for 2019 is awarded to William Kaelin, Jr. , Sir Peter Ratcliffe, and Gregg Semenza on this topic. • Has many current and future applications Ex: anti-VEGF in cancer patients

Background Corneille Heymans ( Noble prize 1938): Blood oxygen sensing via the carotid body controls our respiratory rate by communicating directly with the brain. At the beginning of the 20 th century: Human Hormonal Erythropoietin (EPO) rise in response to Hypoxia EPO gene and how it is regulated by varying oxygen levels Discovery of specific DNA segments located next to the EPO gene

The DNA segments can bind to a protein complex in an oxygen dependent manner and Semenza called it Hypoxia Inducible Factor (HIF). Hypoxia inducible factor In 1995: HIF is composed of two different DNA-binding proteins (transcription factors): HIF-1α and β • HIF-1α : oxygen-regulated α subunit • HIF-1 β : common constitutive β subunit.

Structure of HIF-1α

Regulators and Genes affected Under well-oxygenated conditions, HIF-1 α is bound by the Von Hippel-Lindau (VHL) protein. VHL recruits an ubiquitin ligase that targets HIF-1 α for proteasomal degradation. VHL binding is dependent upon hydroxylation of a specific proline residue in HIF-1 α

Burrows, et al (2011)

Oxygen shifts the balance Iommarini et al

Regulation (Extended) Palazón etal 2014

Genes affected

Role in Angiogenesis

Role in Angiogenesis BMDACs Wang et al(2017)

Role in Metabolic Reprogramming

Cytokines

Role in Cellular Growth and Survival

Role in Cellular Metastasis

Did Amazon forest fires make us question our future? !

References • The Nobel Prize in Physiology or Medicine 2019. Nobel. Prize. org. Nobel Media AB 2019. Wed. 6 Nov 2019 • Gregg L. Semenza (2011): Hypoxia-Inducible Factors in Physiology and Medicine. cell, 148(12), 399 -408. • Muran Zhou, Jinfei Hou, Yuan Li, Shan Mou, Zhenxing Wang, , Raymund E. Horch, Jiaming Sun and Quan Yuan (2019): The pro-angiogenic role of hypoxia inducible factor stabilizer FG-4592 and its application in an in vivo tissue engineering chamber model, Scientific Reports , (9)6035.

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