The Oncogenic RAS2(val19) Mutation Locks Respiration, Independently of PKA, in a Mode Prone to Generate ROS

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2003 Jul 4

PMID 12839995

Citations 42

Authors

Lydie Hlavata

Hugo Aguilaniu

Alena Pichova

Thomas Nystrom

Affiliations

Soon will be listed here.

Abstract

The RAS2(val19) allele, which renders the cAMP-PKA pathway constitutively active and decreases the replicative life-span of yeast cells, is demonstrated to increase production of reactive oxygen species (ROS) and to elevate oxidative protein damage. Mitochondrial respiration in the mutant is locked in a non-phosphorylating mode prone to generate ROS but this phenotype is not linked to a constitutively active PKA pathway. In contrast, providing RAS2(val19) cells with the mammalian uncoupling protein UCP1 restores phosphorylating respiration and reduces ROS levels, but does not correct for PKA-dependent defects. Thus, the RAS2(val19) allele acts like a double-edged sword with respect to oxidation management: (i). it diminishes expression of STRE element genes required for oxidative stress defenses in a PKA-dependent fashion, and (ii). it affects endogenous ROS production and the respiratory state in a PKA-independent way. The effect of the oncogenic RAS allele on the replicative life-span is primarily asserted via the PKA-dependent pathway since Pde2p, but not UCP1, overproduction suppressed premature aging of the RAS2(val19) mutant.

Citing Articles

Antifungal Mechanism of Essential Oil: A Colombian Traditional Alternative against Anthracnose Caused by .

Peralta-Ruiz Y, Hernandez J, Grande-Tovar C, Serio A, Valbonetti L, Chaves-Lopez C Molecules. 2024; 29(15).

PMID: 39124920 PMC: 11314608. DOI: 10.3390/molecules29153516.

Gender Differences in Oxidative Stress in Relation to Cancer Susceptibility and Survival.

Allegra A, Caserta S, Genovese S, Pioggia G, Gangemi S Antioxidants (Basel). 2023; 12(6).

PMID: 37371985 PMC: 10295142. DOI: 10.3390/antiox12061255.

Modulation of Nrf2/HO-1 by Natural Compounds in Lung Cancer.

Ghareghomi S, Moosavi-Movahedi F, Saso L, Habibi-Rezaei M, Khatibi A, Hong J Antioxidants (Basel). 2023; 12(3).

PMID: 36978983 PMC: 10044870. DOI: 10.3390/antiox12030735.

Mitochondrial DNA mutations are involved in the acquisition of cisplatin resistance in human lung cancer A549 cells.

Horibe S, Ishikawa K, Nakada K, Wake M, Takeda N, Tanaka T Oncol Rep. 2021; 47(2).

PMID: 34935060 PMC: 8717125. DOI: 10.3892/or.2021.8243.

Senescent tumor cells: an overlooked adversary in the battle against cancer.

Park S, Choi Y, Kim J, Kim H, Park T Exp Mol Med. 2021; 53(12):1834-1841.

PMID: 34916607 PMC: 8741813. DOI: 10.1038/s12276-021-00717-5.

References

Thevelein J . Signal transduction in yeast. Yeast. 1994; 10(13):1753-90. DOI: 10.1002/yea.320101308. View

Fitton V, Rigoulet M, Ouhabi R, Guerin B . Mechanistic stoichiometry of yeast mitochondrial oxidative phosphorylation. Biochemistry. 1994; 33(32):9692-8. DOI: 10.1021/bi00198a039. View

Parrini M, Bernardi A, Parmeggiani A . Determinants of Ras proteins specifying the sensitivity to yeast Ira2p and human p120-GAP. EMBO J. 1996; 15(5):1107-11. PMC: 450008. View

Marchler G, Schuller C, Ruis H, Estruch F . The Saccharomyces cerevisiae zinc finger proteins Msn2p and Msn4p are required for transcriptional induction through the stress response element (STRE). EMBO J. 1996; 15(9):2227-35. PMC: 450147. View

Bindokas V, Jordan J, Lee C, Miller R . Superoxide production in rat hippocampal neurons: selective imaging with hydroethidine. J Neurosci. 1996; 16(4):1324-36. PMC: 6578569. View

Skulachev V . Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants. Q Rev Biophys. 1996; 29(2):169-202. DOI: 10.1017/s0033583500005795. View

Cain K, Griffiths D . Studies of energy-linked reactions. Localization of the site of action of trialkyltin in yeast mitochondria. Biochem J. 1977; 162(3):575-80. PMC: 1164640. DOI: 10.1042/bj1620575. View

Serrano M, Lin A, McCurrach M, Beach D, Lowe S . Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997; 88(5):593-602. DOI: 10.1016/s0092-8674(00)81902-9. View

Enerback S, Jacobsson A, Simpson E, Guerra C, Yamashita H, Harper M . Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature. 1997; 387(6628):90-4. DOI: 10.1038/387090a0. View

10.

Pichova A, Vondrakova D, Breitenbach M . Mutants in the Saccharomyces cerevisiae RAS2 gene influence life span, cytoskeleton, and regulation of mitosis. Can J Microbiol. 1997; 43(8):774-81. DOI: 10.1139/m97-111. View

11.

Korshunov S, Skulachev V, Starkov A . High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett. 1997; 416(1):15-8. DOI: 10.1016/s0014-5793(97)01159-9. View

12.

Sinclair D, Guarente L . Extrachromosomal rDNA circles--a cause of aging in yeast. Cell. 1998; 91(7):1033-42. DOI: 10.1016/s0092-8674(00)80493-6. View

13.

Skulachev V . Uncoupling: new approaches to an old problem of bioenergetics. Biochim Biophys Acta. 1998; 1363(2):100-24. DOI: 10.1016/s0005-2728(97)00091-1. View

14.

Dukan S, Nystrom T . Bacterial senescence: stasis results in increased and differential oxidation of cytoplasmic proteins leading to developmental induction of the heat shock regulon. Genes Dev. 1998; 12(21):3431-41. PMC: 317226. DOI: 10.1101/gad.12.21.3431. View

15.

GARLID K, Jaburek M, Jezek P . The mechanism of proton transport mediated by mitochondrial uncoupling proteins. FEBS Lett. 1998; 438(1-2):10-4. DOI: 10.1016/s0014-5793(98)01246-0. View

16.

Klingenberg M, Huang S . Structure and function of the uncoupling protein from brown adipose tissue. Biochim Biophys Acta. 1999; 1415(2):271-96. DOI: 10.1016/s0005-2736(98)00232-6. View

17.

Lee A, Fenster B, Ito H, Takeda K, Bae N, Hirai T . Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J Biol Chem. 1999; 274(12):7936-40. DOI: 10.1074/jbc.274.12.7936. View

18.

Kirchman P, Kim S, Lai C, Jazwinski S . Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics. 1999; 152(1):179-90. PMC: 1460582. DOI: 10.1093/genetics/152.1.179. View

19.

Jazwinski S . Molecular mechanisms of yeast longevity. Trends Microbiol. 1999; 7(6):247-52. DOI: 10.1016/s0966-842x(99)01509-7. View

20.

Dukan S, Nystrom T . Oxidative stress defense and deterioration of growth-arrested Escherichia coli cells. J Biol Chem. 1999; 274(37):26027-32. DOI: 10.1074/jbc.274.37.26027. View