Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNTVKVU)

• DOT Name: Growth/differentiation factor 9 (GDF9)
• Synonyms: GDF-9
• Gene Name: GDF9
• Related Disease:
  Neoplasm
  Bladder cancer
  Breast neoplasm
  Clear cell renal carcinoma
  Keloid
  Kidney cancer
  Kidney neoplasm
  Polycystic ovarian syndrome
  Premature ovarian failure 14
  Renal carcinoma
  Shwachman-Diamond syndrome
  Turner syndrome
  Urinary bladder cancer
  Urinary bladder neoplasm
  Adenocarcinoma
  Fetal growth restriction
  Gallbladder carcinoma
  Granulosa cell tumor
  Hereditary hemochromatosis
  Prostate cancer
  Prostate carcinoma
• UniProt ID: GDF9_HUMAN
• Pfam ID: PF00019
• Sequence:
  MARPNKFLLWFCCFAWLCFPISLGSQASGGEAQIAASAELESGAMPWSLLQHIDERDRAG
  LLPALFKVLSVGRGGSPRLQPDSRALHYMKKLYKTYATKEGIPKSNRSHLYNTVRLFTPC
  TRHKQAPGDQVTGILPSVELLFNLDRITTVEHLLKSVLLYNINNSVSFSSAVKCVCNLMI
  KEPKSSSRTLGRAPYSFTFNSQFEFGKKHKWIQIDVTSLLQPLVASNKRSIHMSINFTCM
  KDQLEHPSAQNGLFNMTLVSPSLILYLNDTSAQAYHSWYSLHYKRRPSQGPDQERSLSAY
  PVGEEAAEDGRSSHHRHRRGQETVSSELKKPLGPASFNLSEYFRQFLLPQNECELHDFRL
  SFSQLKWDNWIVAPHRYNPRYCKGDCPRAVGHRYGSPVHTMVQNIIYEKLDSSVPRPSCV
  PAKYSPLSVLTIEPDGSIAYKEYEDMIATKCTCR
• Function: Required for ovarian folliculogenesis. Promotes primordial follicle development. Stimulates granulosa cell proliferation. Promotes cell transition from G0/G1 to S and G2/M phases, through an increase of CCND1 and CCNE1 expression, and RB1 phosphorylation. It regulates STAR expression and cAMP-dependent progesterone release in granulosa and thecal cells. Attenuates the suppressive effects of activin A on STAR expression and progesterone production by increasing the expression of inhibin B. It suppresses FST and FSTL3 production in granulosa-lutein cells.
• Tissue Specificity: Expressed in ovarian granulosa cells. Present in oocytes of primary follicles (at protein level).
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[3]
Keloid	DISV09JY	Strong	Biomarker	[4]
Kidney cancer	DISBIPKM	Strong	Altered Expression	[5]
Kidney neoplasm	DISBNZTN	Strong	Altered Expression	[5]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[6]
Premature ovarian failure 14	DISPUO2J	Strong	Autosomal recessive	[7]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[5]
Shwachman-Diamond syndrome	DISW57NW	Strong	Biomarker	[8]
Turner syndrome	DIS2035C	Strong	Genetic Variation	[9]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[1]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[10]
Fetal growth restriction	DIS5WEJ5	Limited	Altered Expression	[11]
Gallbladder carcinoma	DISD6ACL	Limited	Altered Expression	[10]
Granulosa cell tumor	DISKWVAB	Limited	Genetic Variation	[12]
Hereditary hemochromatosis	DISVG5MT	Limited	Biomarker	[13]
Prostate cancer	DISF190Y	Limited	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[14]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Growth/differentiation factor 9 (GDF9).	[15]

References

• [1] Growth differentiation factor-9 expression is inversely correlated with an aggressive behaviour in human bladder cancer cells.Int J Mol Med. 2012 Mar;29(3):428-34. doi: 10.3892/ijmm.2011.858. Epub 2011 Dec 12.
• [2] The role of growth differentiation factor-9 (GDF-9) and its analog, GDF-9b/BMP-15, in human breast cancer.Ann Surg Oncol. 2007 Jul;14(7):2159-66. doi: 10.1245/s10434-007-9397-5. Epub 2007 Apr 24.
• [3] Reduced expression of growth and differentiation factor-9 (GDF9) is associated with aggressive behaviour of human clear-cell renal cell carcinoma and poor patient survival.Anticancer Res. 2014 Nov;34(11):6515-20.
• [4] Growth Differentiation Factor-9 Promotes Fibroblast Proliferation and Migration in Keloids through the Smad2/3 Pathway.Cell Physiol Biochem. 2016;40(1-2):207-218. doi: 10.1159/000452538. Epub 2016 Nov 18.
• [5] Loss of expression of growth differentiation factor-9 (GDF9) in human kidney cancer and regulation of growth and migration of kidney cancer cells by GDF9.Anticancer Res. 2012 Oct;32(10):4375-83.
• [6] Serum Concentrations of Oocyte-Secreted Factors BMP15 and GDF9 During IVF and in Women With Reproductive Pathologies.Endocrinology. 2019 Oct 1;160(10):2298-2313. doi: 10.1210/en.2019-00264.
• [7] Identification of the first homozygous 1-bp deletion in GDF9 gene leading to primary ovarian insufficiency by using targeted massively parallel sequencing. Clin Genet. 2018 Feb;93(2):408-411. doi: 10.1111/cge.13156. Epub 2017 Dec 26.
• [8] Evaluating two ovarian decellularization methods in three species.Mater Sci Eng C Mater Biol Appl. 2019 Sep;102:670-682. doi: 10.1016/j.msec.2019.04.092. Epub 2019 Apr 30.
• [9] Differentiation of primordial germ cells from premature ovarian insufficiency-derived induced pluripotent stem cells.Stem Cell Res Ther. 2019 May 31;10(1):156. doi: 10.1186/s13287-019-1261-6.
• [10] Expression of CDC6 and GDF-9 and their clinicopathological significances in benign and malignant lesions of the gallbladder.Cancer Biomark. 2012;11(2-3):107-14. doi: 10.3233/CBM-2012-0267.
• [11] Fetal Growth Restriction Is Associated With Decreased Number of Ovarian Follicles and Impaired Follicle Growth in Young Adult Guinea Pig Offspring.Reprod Sci. 2019 Dec;26(12):1557-1567. doi: 10.1177/1933719119828041. Epub 2019 Feb 11.
• [12] Granulosa cell tumor mutant FOXL2C134W suppresses GDF-9 and activin A-induced follistatin transcription in primary granulosa cells.Mol Cell Endocrinol. 2013 Jun 15;372(1-2):57-64. doi: 10.1016/j.mce.2013.03.021. Epub 2013 Apr 6.
• [13] Ovarian Follicular Theca Cell Recruitment, Differentiation, and Impact on Fertility: 2017 Update.Endocr Rev. 2018 Feb 1;39(1):1-20. doi: 10.1210/er.2017-00164.
• [14] GDF-9 promotes the growth of prostate cancer cells by protecting them from apoptosis.J Cell Physiol. 2010 Nov;225(2):529-36. doi: 10.1002/jcp.22235.
• [15] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.