Molecule Information

General Information of the Molecule (ID: Mol01845)

• Name: Protein phosphatase 1 regulatory subunit 15A (PPP1R15A) ,Homo sapiens
• Synonyms: Protein phosphatase 1 regulatory subunit 15A; Growth arrest and DNA damage-inducible protein GADD34; Myeloid differentiation primary response protein MyD116 homolog
• Molecule Type: Protein
• Gene Name: PPP1R15A
• Gene ID: 23645
• Location: chr19:48,872,421-48,876,058[+]
• Sequence:
  MAPGQAPHQATPWRDAHPFFLLSPVMGLLSRAWSRLRGLGPLEPWLVEAVKGAALVEAGL
  EGEARTPLAIPHTPWGRRPEEEAEDSGGPGEDRETLGLKTSSSLPEAWGLLDDDDGMYGE
  REATSVPRGQGSQFADGQRAPLSPSLLIRTLQGSDKNPGEEKAEEEGVAEEEGVNKFSYP
  PSHRECCPAVEEEDDEEAVKKEAHRTSTSALSPGSKPSTWVSCPGEEENQATEDKRTERS
  KGARKTSVSPRSSGSDPRSWEYRSGEASEEKEEKAHKETGKGEAAPGPQSSAPAQRPQLK
  SWWCQPSDEEEGEVKALGAAEKDGEAECPPCIPPPSAFLKAWVYWPGEDTEEEEDEEEDE
  DSDSGSDEEEGEAEASSSTPATGVFLKSWVYQPGEDTEEEEDEDSDTGSAEDEREAETSA
  STPPASAFLKAWVYRPGEDTEEEEDEDVDSEDKEDDSEAALGEAESDPHPSHPDQRAHFR
  GWGYRPGKETEEEEAAEDWGEAEPCPFRVAIYVPGEKPPPPWAPPRLPLRLQRRLKRPET
  PTHDPDPETPLKARKVRFSEKVTVHFLAVWAGPAQAARQGPWEQLARDRSRFARRITQAQ
  EELSPCLTPAARARAWARLRNPPLAPIPALTQTLPSSSVPSSPVQTTPLSQAVATPSRSS
  AAAAAALDLSGRRG
• 3D-structure: PDB ID: 4XPN; Classification: Hydrolase; Method: X-ray diffraction; Resolution: 2.29 Å
• Function: Recruits the serine/threonine-protein phosphatase PPP1CA to prevents excessive phosphorylation of the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases and facilitating recovery of cells from stress. Down-regulates the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 by PP1. May promote apoptosis by inducing p53/TP53 phosphorylation on 'Ser-15'. Plays an essential role in autophagy by tuning translation during starvation, thus enabling lysosomal biogenesis and a sustained autophagic flux. Acts also a viral restriction factor by attenuating HIV-1 replication. Mechanistically, mediates the inhibition of HIV-1 TAR RNA-mediated translation.
• Uniprot ID: PR15A_HUMAN
• Ensembl ID: ENSG00000087074
• HGNC ID: HGNC:14375

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Cytarabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [1]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Cytarabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: DNA Damage Response Mechanism; Regulation; N.A.
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: TF-1 cells; Blood; Homo sapiens (Human); CVCL_0559
• Experiment for Molecule Alteration: RT-qPCR; Western blot assay
• Experiment for Drug Resistance: MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
• Mechanism Description: DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress. Especially, PPP1R15A is mainly involved in the recovery of the cells from stress and it was the only DDR gene upregulated in AML patients.

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [1]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Cytarabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: DNA Damage Response Mechanism; Regulation; N.A.
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: TF-1 cells; Blood; Homo sapiens (Human); CVCL_0559
• Experiment for Molecule Alteration: RT-qPCR; Western blot assay
• Experiment for Drug Resistance: MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
• Mechanism Description: DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress.Using PCR arrays we observed an upregulation of of several DDR genes (CDKN1A, GADD45A, GADD45G, EXO1, and PPP1R15A) in KASUMI-1 and MV4-11 cell lines that survived following treatment with Idarubicin and Cytarabine.

Idarubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [1]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Idarubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: DNA Damage Response Mechanism; Regulation; N.A.
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: TF-1 cells; Blood; Homo sapiens (Human); CVCL_0559
• Experiment for Molecule Alteration: RT-qPCR; Western blot assay
• Experiment for Drug Resistance: MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
• Mechanism Description: DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress. Especially, PPP1R15A is mainly involved in the recovery of the cells from stress and it was the only DDR gene upregulated in AML patients.

Investigative Drug(s) 1 drug(s) in total

Bevacizumab/FOLFIRI Regimen

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [2]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Bevacizumab/FOLFIRI Regimen
• Molecule Alteration: Missense mutation; p.R251P (c.752G>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTT assay

References

• Ref 1: Silencing of the DNA damage repair regulator PPP1R15A sensitizes acute myeloid leukemia cells to chemotherapy. Ann Hematol. 2024 Aug;103(8):2853-2863.
• Ref 2: Feasibility of novel PPP1R15A and proposed ANXA11 single nucleotide polymorphisms as predictive markers for bevacizumab regimen in metastatic colorectal cancerJ Cancer Res Clin Oncol. 2016 Aug;142(8):1705-14. doi: 10.1007/s00432-016-2177-5. Epub 2016 May 13.