Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT12KOD)

• DTT Name: P53 messenger RNA (TP53 mRNA)
• Synonyms: Tumor suppressor p53 (mRNA); Phosphoprotein p53 (mRNA); P53 (mRNA); Antigen NY-CO-13 (mRNA)
• Gene Name: TP53
• DTT Type: Clinical trial target; [1]
• BioChemical Class: mRNA target
• UniProt ID: P53_HUMAN
• TTD ID: T82051
• Sequence:
  MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGP
  DEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAK
  SVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHE
  RCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNS
  SCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELP
  PGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPG
  GSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD
• Function: Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2. Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Sphingolipid signaling pathway (hsa04071)
  Cell cycle (hsa04110)
  p53 signaling pathway (hsa04115)
  PI3K-Akt signaling pathway (hsa04151)
  Apoptosis (hsa04210)
  Wnt signaling pathway (hsa04310)
  Neurotrophin signaling pathway (hsa04722)
  Thyroid hormone signaling pathway (hsa04919)
  Amyotrophic lateral sclerosis (ALS) (hsa05014)
  Huntington's disease (hsa05016)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  HTLV-I infection (hsa05166)
  Herpes simplex infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Viral carcinogenesis (hsa05203)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
  Colorectal cancer (hsa05210)
  Pancreatic cancer (hsa05212)
  Endometrial cancer (hsa05213)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Thyroid cancer (hsa05216)
  Basal cell carcinoma (hsa05217)
  Melanoma (hsa05218)
  Bladder cancer (hsa05219)
  Chronic myeloid leukemia (hsa05220)
  Small cell lung cancer (hsa05222)
  Non-small cell lung cancer (hsa05223)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  Activation of PUMA and translocation to mitochondria (R-HSA-139915)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  Formation of Senescence-Associated Heterochromatin Foci (SAHF) (R-HSA-2559584)
  Oncogene Induced Senescence (R-HSA-2559585)
  DNA Damage/Telomere Stress Induced Senescence (R-HSA-2559586)
  Autodegradation of the E3 ubiquitin ligase COP1 (R-HSA-349425)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Stabilization of p53 (R-HSA-69541)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  Activation of NOXA and translocation to mitochondria (R-HSA-111448)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cenersen	DMMN21R	Acute myeloid leukaemia	2A60	Phase 2	[2]
OPI-1002	DML6TAS	Acute kidney injury	GB60	Phase 2	[1]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AHL	DMVZLIB	Hearing disorder	AB50-AB57	Investigative	[2]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2C82	Bone marrow	7.90E-07	0.3	0.59

References

• [1] 2011 Pipeline of Quark Pharm.
• [2] Phase 2 randomized study of p53 antisense oligonucleotide (cenersen) plus idarubicin with or without cytarabine in refractory and relapsed acute myeloid leukemia. Cancer. 2012 Jan 15;118(2):418-27.