Regulatory feedback loop between TP73 and TRIM32

Abstract

The p73 transcription factor is one of the members of the p53 family of tumor suppressors with unique biological functions in processes like neurogenesis, embryonic development and differentiation. For this reason, p73 activity is tightly regulated by multiple mechanisms, including transcription and post-translational modifications. Here, we identified a novel regulatory loop between TAp73 and the E3 ubiquitin ligase tripartite motif protein 32 (TRIM32). TRIM32, a new direct p73 transcriptional target in the context of neural progenitor cells, is differentially regulated by p73. Although TAp73 binds to the TRIM32 promoter and activates its expression, TAp73-induced TRIM32 expression is efficiently repressed by DNp73. TRIM32 in turn physically interacts with TAp73 and promotes its ubiquitination and degradation, impairing p73-dependent transcriptional activity. This mutual regulation between p73 and TRIM32 constitutes a novel feedback loop, which might have important implications in central nervous system development as well as relevance in oncogenesis, and thus emerges as a possible therapeutic target.

E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis

“…17 Most recently, p73 was reported to upregulate the basal levels of TRIM32, and furthermore, TRIM32 ubiquitinates p73 in neuronal cells, which might contribute to TRIM32's function in neuronal development and differentiation. 41 The regulation of TRIM32 by p53 and p73 appears to be different and highly context dependent. For instance, the induction of TRIM32 by p73 was observed in neuronal cells, but not in the cancer cell lines that showed the upregulation of TRIM32 by p53 activation in response to stress in this study.…”

“…This result is consistent with a recent report showing that TRIM32 degrades p73 in neuronal cells. 41 Furthermore, TRIM32 displayed a stronger effect on p53 than on TA-p63a or TA-p73a as shown in both HCT116 p53 þ / þ and H1299 cells (Supplementary Figures 9a and b). These results suggested that the downregulation of p53 by TRIM32 mainly contributes to TRIM32's function in downregulating apoptosis, cell cycle arrest and senescence in response to stress.…”

Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing

“…One can hypothesize that the complete loss of function of TRIM32 could affect the cognitive functions as TRIM32 has previously shown to be involved in neuronal differentiation. [20][21][22][23] Alternatively, the cognitive impairment may be related to the fact that the deletion also includes part of the ASTN2 gene that codes for astrotactin 2, a brain protein possibly involved in neuronal migration. 11 A recent large study revealed that heterozygous copy number variations affecting the 3′-terminal part of ASTN2 or both ASTN2 and TRIM32 are significantly enriched in males with neurodevelopmental and neurobehavioral disorders.…”

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

“…While Itch is basically ubiquitous, the expression of the p53 family members, that is p63 and p73, [63][64][65][66][67][68] is strictly tissue-and cellspecific; moreover several disorders known as ectodermal dysplasias 12,[69][70][71][72][73][74][75] as well as cancer show a deregulated expression levels of p63 and p73. 39,76 Physiologically, p63 and p73 protein levels are normally kept under strict control through Itch-mediated ubiquitylation, and indeed both p63 and p73 have a canonical PY motif (absent in p53 which is regulated by a different E3 ligase) located in their C-terminal which accounts for the binding to Itch through its WW domains.…”