HOPS and p53: thick as thieves in life and death

Abstract

The oncosuppressor protein p53 plays a major role in transcriptionally controlling the expression of a number of genes, which in turn regulates many functions in response to DNA damage, oncogene triggering, oxidative, and additional cell stresses. A developing area of interest in p53 is the studies related to its cytoplasmic function(s). Many investigations revealed the significant role of p53 in the cytoplasm, acting in a transcriptional-independent manner in important processes related to cell homeostasis such as; apoptosis, autophagy, metabolism control, drug, and oxidative stress response. The studies on cytoplasmic p53 have shown intricate mechanisms by which posttranslational modifications allow p53 to perform its cytoplasmic functions. A number of ubiquitins, deubiquitins, and small ubiquitin-like proteins, have a pivotal role in controlling cytoplasmic stability and localization. Recently, HOPS/TMUB1 a novel small ubiquitin-like protein has been described as a vital molecule stabilizing p53 half-life, directing it to the mitochondria and favoring p53-mediated apoptosis. Furthermore, HOPS/TMUB1 competing with importin-α lessens p53 nuclear localization, thereby increasing cytoplasmic concentration. HOPS/TMUB1 as p53 modifiers could be attractive candidates to elucidate apoptosis or other important transcriptional-independent functions which are key in cancer research in order to develop new therapeutic approaches.

Keywords: Apoptosis; Hepatocyte Odd Protein Shuttling (HOPS); Liver regeneration; Mitochondrial Apoptosis; Nucleophosmin (NPM)/p19 Arf; Transmembrane and ubiquitin-like domain containing 1 (TMUB1); Tumor Suppressor Gene; Ubiquitin–Like Protein; p53.

Figure 1.

Schematic representation of the different activities of p53

Figure 2.

HOPS crosstalk with other p53 modulators

Figure 3.

Overview of HOPS impact on p53 activity in the cellHOPS is concerned in lengthening of p53 half-life inhibiting MDM2 E3 ligase activity. Upon DNA damage stresses, HOPS enhances p53 stability sustaining p53 cytoplasmic pool. Cytoplasmic p53 is than available for mitochondrial translocation and MOMP induction for apoptotic outcome. Moreover, HOPS can modulate importin α binding to p53, responsible for p53 nuclear import, thus reducing p53 transcriptional activation (upper panel). In the absence of HOPS apoptotic response to DNA damage inputs is reduced. In HOPS^−/- models p53 half-life is shortened leading to cytoplasmic pool drop and in turn reduced mitochondrial apoptosis. Importin α binding to p53 is not hampered by HOPS competition and nuclear import is increased (bottom panel)