UBE4B: a Promising Regulatory Molecule in Neuronal Death and Survival

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2012 Dec 11

PMID 23222733

Citations 6

Authors

Rami Abou Zeinab

Hong Wu

Consolato Sergi

Roger Leng

Affiliations

Soon will be listed here.

Abstract

Neuronal survival and death of neurons are considered a fundamental mechanism in the regulation of the nervous system during early development of the system and in adulthood. Defects in this mechanism are highly problematic and are associated with many neurodegenerative diseases. Because neuronal programmed death is apoptotic in nature, indicating that apoptosis is a key regulatory process, the p53 family members (p53, p73, p63) act as checkpoints in neurons due to their role in apoptosis. The complexity of this system is due to the existence of different naturally occurring isoforms that have different functions from the wild types (WT), varying from apoptotic to anti-apoptotic effects. In this review, we focus on the role of UBE4B (known as Ube4b or Ufd2a in mouse), an E3/E4 ligase that triggers substrate polyubiquitination, as a master regulatory ligase associated with the p53 family WT proteins and isoforms in regulating neuronal survival. UBE4B is also associated with other pathways independent of the p53 family, such as polyglutamine aggregation and Wallerian degeneration, both of which are critical in neurodegenerative diseases. Many of the hypotheses presented here are gateways to understanding the programmed death/survival of neurons regulated by UBE4B in normal physiology, and a means of introducing potential therapeutic approaches with implications in treating several neurodegenerative diseases.

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References

Jacobs W, Govoni G, Ho D, Atwal J, Barnabe-Heider F, Keyes W . p63 is an essential proapoptotic protein during neural development. Neuron. 2005; 48(5):743-56. DOI: 10.1016/j.neuron.2005.10.027. View

Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P . p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003; 11(3):577-90. DOI: 10.1016/s1097-2765(03)00050-9. View

Yang Y, Li C, Weissman A . Regulating the p53 system through ubiquitination. Oncogene. 2004; 23(11):2096-106. DOI: 10.1038/sj.onc.1207411. View

Saeki Y, Kudo T, Sone T, Kikuchi Y, Yokosawa H, Toh-E A . Lysine 63-linked polyubiquitin chain may serve as a targeting signal for the 26S proteasome. EMBO J. 2009; 28(4):359-71. PMC: 2646160. DOI: 10.1038/emboj.2008.305. View

Zeng X, Chen L, Jost C, Maya R, Keller D, Wang X . MDM2 suppresses p73 function without promoting p73 degradation. Mol Cell Biol. 1999; 19(5):3257-66. PMC: 84120. DOI: 10.1128/MCB.19.5.3257. View

Laser H, Conforti L, Morreale G, Mack T, Heyer M, Haley J . The slow Wallerian degeneration protein, WldS, binds directly to VCP/p97 and partially redistributes it within the nucleus. Mol Biol Cell. 2005; 17(3):1075-84. PMC: 1382299. DOI: 10.1091/mbc.e05-04-0375. View

Ozeki C, Sawai Y, Shibata T, Kohno T, Okamoto K, Yokota J . Cancer susceptibility polymorphism of p53 at codon 72 affects phosphorylation and degradation of p53 protein. J Biol Chem. 2011; 286(20):18251-60. PMC: 3093897. DOI: 10.1074/jbc.M110.208587. View

Kaneko C, Hatakeyama S, Matsumoto M, Yada M, Nakayama K, Nakayama K . Characterization of the mouse gene for the U-box-type ubiquitin ligase UFD2a. Biochem Biophys Res Commun. 2002; 300(2):297-304. DOI: 10.1016/s0006-291x(02)02834-6. View

Aloyz R, Bamji S, Pozniak C, Toma J, Atwal J, Kaplan D . p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors. J Cell Biol. 1998; 143(6):1691-703. PMC: 2132983. DOI: 10.1083/jcb.143.6.1691. View

10.

Chatterjee A, Upadhyay S, Chang X, Nagpal J, Trink B, Sidransky D . U-box-type ubiquitin E4 ligase, UFD2a attenuates cisplatin mediated degradation of DeltaNp63alpha. Cell Cycle. 2008; 7(9):1231-7. PMC: 3073353. DOI: 10.4161/cc.7.9.5795. View

11.

Donehower L, Harvey M, Slagle B, McArthur M, Montgomery Jr C, Butel J . Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992; 356(6366):215-21. DOI: 10.1038/356215a0. View

12.

Lee Y, McKinnon P . Detection of apoptosis in the central nervous system. Methods Mol Biol. 2009; 559:273-82. PMC: 3042270. DOI: 10.1007/978-1-60327-017-5_19. View

13.

Morreale G, Conforti L, Coadwell J, Wilbrey A, Coleman M . Evolutionary divergence of valosin-containing protein/cell division cycle protein 48 binding interactions among endoplasmic reticulum-associated degradation proteins. FEBS J. 2009; 276(5):1208-20. DOI: 10.1111/j.1742-4658.2008.06858.x. View

14.

Hosoda M, Ozaki T, Miyazaki K, Hayashi S, Furuya K, Watanabe K . UFD2a mediates the proteasomal turnover of p73 without promoting p73 ubiquitination. Oncogene. 2005; 24(48):7156-69. DOI: 10.1038/sj.onc.1208872. View

15.

Lunn E, Perry V, Brown M, Rosen H, Gordon S . Absence of Wallerian Degeneration does not Hinder Regeneration in Peripheral Nerve. Eur J Neurosci. 1989; 1(1):27-33. DOI: 10.1111/j.1460-9568.1989.tb00771.x. View

16.

Osada M, Inaba R, Shinohara H, Hagiwara M, Nakamura M, Ikawa Y . Regulatory domain of protein stability of human P51/TAP63, a P53 homologue. Biochem Biophys Res Commun. 2001; 283(5):1135-41. DOI: 10.1006/bbrc.2001.4905. View

17.

Watanabe H, Ohta S, Kumon Y, Sakaki S, Sakanaka M . Increase in p53 protein expression following cortical infarction in the spontaneously hypertensive rat. Brain Res. 1999; 837(1-2):38-45. DOI: 10.1016/s0006-8993(99)01652-2. View

18.

Johnstone R, Ruefli A, Lowe S . Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002; 108(2):153-64. DOI: 10.1016/s0092-8674(02)00625-6. View

19.

Pelosi G, Pasini F, Olsen Stenholm C, Pastorino U, Maisonneuve P, Sonzogni A . p63 immunoreactivity in lung cancer: yet another player in the development of squamous cell carcinomas?. J Pathol. 2002; 198(1):100-9. DOI: 10.1002/path.1166. View

20.

Wu H, Abou Zeinab R, Flores E, Leng R . Pirh2, a ubiquitin E3 ligase, inhibits p73 transcriptional activity by promoting its ubiquitination. Mol Cancer Res. 2011; 9(12):1780-90. DOI: 10.1158/1541-7786.MCR-11-0157. View