STEAP3 (TSAP6) forms a complex with a pro-apoptotic protein BNIP3L (NIX) and cooperates with BNIP3L in promoting apoptosis, but the exact mechanism is not known (Passer et al. 2003).

While STEAP3 localizes to endosome membranes, BNIP3L localizes to the outer mitochondrial membrane. BNIP3L has recently been implicated in the relocalization of endo-lysosomes to inner mitochondrial compartments, which can play a role in endo-lysosomal processing of mitochondria (Hamacher-Brady et al. 2014).

Binding of TP53 (p53) to the p53 response element in the promoter of the STEAP3 (TSAP6) gene promotes STEAP3 transcription (Passer et al. 2003). Tumor suppressor-activated pathway 6 (TSAP6) was initially discovered as differentially regulated following p53 activation and was later shown to be strongly activated in tumor suppression and reversion, and was hence named TSAP6. TSAP6 knockdown results in inhibition of apoptosis. TSAP6 binds to and cooperates with BNIP3L (NIX), a pro-apoptotic BH3-only BCL2-family member, and MYT1 kinase, a negative regulator of the G2/M transition (Lespagnol et al. 2008).

TP53 (p53) binds the p53 response element in the promoter of the STEAP3 (TSAP6) gene (Passer et al. 2003).

The iron ions that are no longer bound to transferrin are reduced by the metalloreductases STEAP3 and STEAP4, two endosomal membrane proteins, while they are transported through the membrane. The electron donor partner of the enzyme is NADPH (Ohgami et al., 2005; Ohgami et al., 2006; Kleven et al., 2015; Oosterheert et al., 2018).

Active GTP bound RHOD binds to the following effectors at the plasma membrane:
DIAPH1 (Kyrkou et al. 2013)
PAK6 (Durkin et al. 2017)
PLXNA1 (Zanata et al. 2002)
PLXNB1 (Tong et al. 2007)

The following candidate RHOD effectors that can localize to plasma membrane and cytosol were reported in the high throughput screen by Bagci et al. 2020:
ACTN1 (Bagci et al. 2020)
ADD3 (Bagci et al. 2020)
AKAP12 (Bagci et al. 2020)
ARHGAP1 (Bagci et al. 2020)
ARHGAP39 (Bagci et al. 2020)
CAPZB (Bagci et al. 2020)
CAV1 (Bagci et al. 2020)
CPNE8 (Bagci et al. 2020)
DBN1 (Bagci et al. 2020)
DIAPH3 (Bagci et al. 2020)
EFHD2 (Bagci et al. 2020)
ESYT1 (Bagci et al. 2020)
LMNB1 (Bagci et al. 2020)
MCAM (Bagci et al. 2020)
RAB7A (Bagci et al. 2020)
SLC4A7 (Bagci et al. 2020)
STBD1 (Bagci et al. 2020)
STEAP3 (Bagci et al. 2020)
TMPO (Bagci et al. 2020)
TOR1AIP1 (Bagci et al. 2020)
VAMP3 (Bagci et al. 2020)
VANGL1 (Bagci et al. 2020)

The following putative effectors do not bind to active RHOD:
ACTB (Bagci et al. 2020)
BASP1 (Bagci et al. 2020)
FAM169A (Bagci et al. 2020)
MTMR1 (Bagci et al. 2020)
POTEE (Bagci et al. 2020)
SENP1 (Bagci et al. 2020)
SNAP23 (Bagci et al. 2020)
SOWAHC (Bagci et al. 2020)

Apoptotic transcriptional targets of TP53 include genes that regulate the permeability of the mitochondrial membrane and/or cytochrome C release, such as BAX, BID, PMAIP1 (NOXA), BBC3 (PUMA) and probably BNIP3L, AIFM2, STEAP3, TRIAP1 and TP53AIP1 (Miyashita and Reed 1995, Oda et al. 2000, Samuels-Lev et al. 2001, Nakano and Vousden 2001, Sax et al. 2002, Passer et al. 2003, Bergamaschi et al. 2004, Li et al. 2004, Fei et al. 2004, Wu et al. 2004, Park and Nakamura 2005, Patel et al. 2008, Wang et al. 2012, Wilson et al. 2013), thus promoting the activation of the apoptotic pathway.

Transcriptional activation of TP53AIP1 requires phosphorylation of TP53 at serine residue S46 (Oda et al. 2000, Taira et al. 2007). Phosphorylation of TP53 at S46 is regulated by another TP53 pro-apoptotic target, TP53INP1 (Okamura et al. 2001, Tomasini et al. 2003).

The tumor suppressor TP53 (p53) exerts its tumor suppressive role in part by regulating transcription of a number of genes involved in cell death, mainly apoptotic cell death. The majority of apoptotic genes that are transcriptional targets of TP53 promote apoptosis, but there are also several TP53 target genes that inhibit apoptosis, providing cells with an opportunity to attempt to repair the damage and/or recover from stress.
Pro-apoptotic transcriptional targets of TP53 involve TRAIL death receptors TNFRSF10A (DR4), TNFRSF10B (DR5), TNFRSF10C (DcR1) and TNFRSF10D (DcR2), as well as the FASL/CD95L death receptor FAS (CD95). TRAIL receptors and FAS induce pro-apoptotic signaling in response to external stimuli via extrinsic apoptosis pathway (Wu et al. 1997, Takimoto et al. 2000, Guan et al. 2001, Liu et al. 2004, Ruiz de Almodovar et al. 2004, Liu et al. 2005, Schilling et al. 2009, Wilson et al. 2013). IGFBP3 is a transcriptional target of TP53 that may serve as a ligand for a novel death receptor TMEM219 (Buckbinder et al. 1995, Ingermann et al. 2010).

TP53 regulates expression of a number of genes involved in the intrinsic apoptosis pathway, triggered by the cellular stress. Some of TP53 targets, such as BAX, BID, PMAIP1 (NOXA), BBC3 (PUMA) and probably BNIP3L, AIFM2, STEAP3, TRIAP1 and TP53AIP1, regulate the permeability of the mitochondrial membrane and/or cytochrome C release (Miyashita and Reed 1995, Oda et al. 2000, Samuels-Lev et al. 2001, Nakano and Vousden 2001, Sax et al. 2002, Passer et al. 2003, Bergamaschi et al. 2004, Li et al. 2004, Fei et al. 2004, Wu et al. 2004, Park and Nakamura 2005, Patel et al. 2008, Wang et al. 2012, Wilson et al. 2013). Other pro-apoptotic genes, either involved in the intrinsic apoptosis pathway, extrinsic apoptosis pathway or pyroptosis (inflammation-related cell death), which are transcriptionally regulated by TP53 are cytosolic caspase activators, such as APAF1, PIDD1, and NLRC4, and caspases themselves, such as CASP1, CASP6 and CASP10 (Lin et al. 2000, Robles et al. 2001, Gupta et al. 2001, MacLachlan and El-Deiry 2002, Rikhof et al. 2003, Sadasivam et al. 2005, Brough and Rothwell 2007).

It is uncertain how exactly some of the pro-apoptotic TP53 targets, such as TP53I3 (PIG3), RABGGTA, BCL2L14, BCL6, NDRG1 and PERP contribute to apoptosis (Attardi et al. 2000, Guo et al. 2001, Samuels-Lev et al. 2001, Contente et al. 2002, Ihrie et al. 2003, Bergamaschi et al. 2004, Stein et al. 2004, Phan and Dalla-Favera 2004, Jen and Cheung 2005, Margalit et al. 2006, Zhang et al. 2007, Saito et al. 2009, Davies et al. 2009, Giam et al. 2012).

TP53 is stabilized in response to cellular stress by phosphorylation on at least serine residues S15 and S20. Since TP53 stabilization precedes the activation of cell death genes, the TP53 tetramer phosphorylated at S15 and S20 is shown as a regulator of pro-apoptotic/pro-cell death genes. Some pro-apoptotic TP53 target genes, such as TP53AIP1, require additional phosphorylation of TP53 at serine residue S46 (Oda et al. 2000, Taira et al. 2007). Phosphorylation of TP53 at S46 is regulated by another TP53 pro-apoptotic target, TP53INP1 (Okamura et al. 2001, Tomasini et al. 2003). Additional post-translational modifications of TP53 may be involved in transcriptional regulation of genes presented in this pathway and this information will be included as evidence becomes available.

Activation of some pro-apoptotic TP53 targets, such as BAX, FAS, BBC3 (PUMA) and TP53I3 (PIG3) requires the presence of the complex of TP53 and an ASPP protein, either PPP1R13B (ASPP1) or TP53BP2 (ASPP2) (Samuels-Lev et al. 2001, Bergamaschi et al. 2004, Patel et al. 2008, Wilson et al. 2013), indicating how the interaction with specific co-factors modulates the cellular response/outcome.

TP53 family members TP63 and or TP73 can also activate some of the pro-apoptotic TP53 targets, such as FAS, BAX, BBC3 (PUMA), TP53I3 (PIG3), CASP1 and PERP (Bergamaschi et al. 2004, Jain et al. 2005, Ihrie et al. 2005, Patel et al. 2008, Schilling et al. 2009, Celardo et al. 2013).

For a review of the role of TP53 in apoptosis and pro-apoptotic transcriptional targets of TP53, please refer to Riley et al. 2008, Murray-Zmijewski et al. 2008, Bieging et al. 2014, Kruiswijk et al. 2015.