Apoptosis and survival - p53-dependent apoptosis

p53-dependent apoptosis

Direct DNA damage by ionizing radiation or UV can activates the interconnected apoptotic pathways by stimulation of protein kinases from phosphoinositide-3-kinases family. These stimulated kinases directly or indirectly activate phosphorylation of proteins from apoptotic pathways: tumor suppressor p53, breast and ovarian cancer susceptibility protein 1 (Brca1), E2F transcription factor 1 (E2F1), proto-oncogene tyrosine-protein kinase c-Abl and cell cycle regulator RAD9. [1], [2]

Stimulated Brca1 and p53 excite transcription of growth arrest and DNA-damage-inducible transcripts alpha and beta (GADD45 alpha/beta). GADD45alpha/beta triggers apoptosis through activation of mitogen-activated protein kinase kinase kinase 4 (MEKK4)/ mitogen-activated protein kinase kinase 4 (MKK4) or mitogen-activated protein kinase kinase 7 (MKK7)/ c-Jun N-terminal kinase/stress-activated protein kinase (JNK) cascade and/or MEKK4 / MKK4 or MKK7 / mitogen-activated protein kinase 14 (p38 alpha) cascade. [1], [3], [4]

JNK and p38 alpha activate transcription of c-Jun, which, in turn, excites transcription of cyclin-dependent kinase 1 (CDK1). [5] CDK1 catalyzes phosphorylation of the Bcl-2 - antagonist of cell death protein (BAD) at a distinct site, serine 128, and thereby induces BAD-mediated apoptosis. [6] Moreover, JNK stimulates activity of proapoptotic proteins, Bcl-2 modifying factor (BMF) and BCL2-like 11 factor (Bim). [7]

JNK phosphorylates 14-3-3 protein, type sigma (14-3-3 sigma) and stimulates the break of the links between 14-3-3 sigma and c-Alb and between 14-3-3 sigma and Bcl-2 - associated X protein (Bax), that result in activation c-Alb and Bax. Activated c-Alb participates in apoptotic pathways (e.g. via phosphorylation tumor p53-related protein (p73) [8], transcription factor c-Jun or apoptosis-related cysteine protease 9 (Caspase-9). [9]

In addition, c-Alb activates protein kinase C, delta (PKC delta). [10] PKC- delta and ATM may activate by phosphorylation RAD9. RAD9, BAD and BMF are bound with B-cell lymphoma protein 2 (Bcl-2) and inhibit its anti-apoptosis activity.

Nuclear protein p53 plays an important role in apoptosis. The basal p53-Mdm2 loop is an essential component of p53 regulation is. The ubiquitin-protein ligase E3 Mdm2 protein ubiquitinates and promotes degradation of p53. On the other hand, the mdm2 gene is the direct target for binding and transcriptional activation by p53. [11] c-Abl neutralizes the inhibitory effect of Mdm2 on p53. [12], [13] In addition, during indirect activation of p53, E2F1 excite the transcription of cyclin-dependent kinase inhibitor 2A (p14ARF), which interacts with Mdm2 and blocks the ability of Mdm2 to target p53 for destruction. [14] p53 may be activated by component of Brca1/BARD1 complex, BARD1 too. [15]

Activated p53 regulates transcription of apoptosis regulator Bax [16], apoptotic protease activating factor (Apaf-1) [17] and Bcl-2. [18]

E2F may activate apoptosis pathways by stimulation of p53 14-3-3 protein, type tau (14-3-3 tau) is required for expression and induction of E2F1 apoptotic targets, such as p73, Apaf-1, and apoptosis-related cysteine protease 3 (Caspase-3). {PMID: 15494392}

References:

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