TAp73alpha protects small cell lung carcinoma cells from caspase-2 induced mitochondrial mediated apoptotic cell death

Abstract

Caspase-2 is ubiquitously expressed and the most evolutionarily conserved mammalian caspase. It can be activated by a range of death stimuli prior to Bax activation and the occurrence of apoptotic mitochondrial dysfunctions. Caspase-2 has also been reported to exert tumour suppressor function in vivo. The full length TAp73alpha isoform is found up-regulated in various tumour types, and is reported in a cell-type specific manner to repress drug-induced apoptosis. Here, we report that TAp73alpha represses caspase-2 enzymatic activity and by this means reduce caspase-2 induced Bax activation, loss of mitochondrial transmembrane potential and resulting apoptosis. The inhibitory effect on caspase-2 requires the presence of the DNA binding domain and SAM domain region of TAp73alpha. In conclusion, the ability of TAp73alpha to act as an inhibitor of caspase-2-induced cell death together with its up-regulation in certain tumour types strengthen the potential oncogenic activities for this protein.

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

“…[11][12][13][14][15] It is involved in several biological processes, such as cell death, [16][17][18][19] differentiation, [20][21][22] neuronal stem cell maintenance, [23][24][25][26] the amino acid Glutamine is converted into Glutamate by a deamidation reaction catalyzed by the enzyme Glutaminase (GLS). two isoforms of this enzyme have been described, and the GLS2 isoform is regulated by the tumor suppressor gene p53.…”

Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation

“…However, cell growth was also reduced after knockdown of TP73 in cells without Omomyc, indicating that high levels of TP73 are required for cell survival (Figure 8D ). Previously, it was reported that TP73 alpha has an anti-apoptotic effect in SCLC cells, whereas TP73 beta has a pro-apoptotic effect [ 41 ]. Since both isoforms are targeted by the treatment with siRNA, it was likely that apoptosis was induced by the reduced TP73 alpha expression independently of Omomyc (Figure 8E ).…”

Mechanisms, function and clinical applications of DNp73

“…transactivation domain and inhibit TAp73 and p53 activity. [3][4][5][6][7] While much is known about the TAp73 expression in cancer, the effect of DNp73 status on other biological function is less well understood. The aim of this review is to summarize DNp73 expression status in cancer in the current literature.…”

“…p73, like its homolog, the tumor suppressor p53, may act as transcription factors with common target sequences whose transcriptional activation can lead to cell cycle arrest and apoptosis. 6,27,41,42 This property is important for the involvement of p73 in cancer development and therapy. However, in contrast with p53, while the transactivation-proficient TAp73 shows pro-apoptotic effects, the DNp73 has an anti-apoptotic function.…”