The Q205LGo-alpha subunit expressed in NIH-3T3 cells induces transformation

Kroll, Spencer D.; Chen, Jianghao; Vivo, Michael De; Carty, D. J.; Buku, Angeliki; Premont, Richard T.; Iyengar, Ravi

doi:10.1016/s0021-9258(18)50074-0

Cited by 55 publications

(7 citation statements)

References 27 publications

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“…On the basis of previous studies, mutations of GNAO1 are often associated with epileptic encephalopathy and movement disorders. 16,26,39 Although the GNAO1 R243H mutation was found in breast cancer 20 and overexpression of the GNAO1 Q205L mutant promoted NIH-3T3 fibroblast neoplastic transformation in vitro, 18 there has been no evidence to show that a GNAO1 mutant has been characterized as an oncogene in vivo. In this study, we identified the GNAO1 R209C mutant as a driver of childhood leukemia.…”

Section: Discussionmentioning

confidence: 99%

“…Because GNAO1 point mutations, such as G184S, G203R, 15,16 R243H, 20 and Q205L, 18 are important in the development of cancer and diseases (Figure 2A), we analyzed whole-exome sequencing data for 102 AML and 106 ALL samples to examine the prevalence of GNAO1 mutations in a general population of patients with leukemia. We identified only 3 novel somatic GNAO1 mutations in patients with ALL (Figure 2A; supplemental Table 2).…”

Section: Gnao1 Missense Mutations In Patients With Allmentioning

confidence: 99%

“…12 Mutations in Ga proteins have been identified in human tumors and promote malignant transformation and tumorigenesis by rendering the G proteins constitutively active in the GTP-bound conformation, such as GNAS (Ga s ) in pituitary adenomas 13,14 and GNAQ (Gaq) and GNA11 in uveal melanoma. 7,8 Although mutations in GNAO1 have been found to be related to early infantile epileptic encephalopathy and movement disorder [15][16][17] and have been described to be oncogenic when artificially introduced into cultured cells, [18][19][20] no such mutations in GNAO1 have been functionally characterized in human cancers.…”

Section: Introductionmentioning

confidence: 99%

“…(A)The type and position of each GNAO1 mutation with or without the ETV6-RUNX1 (E/V) fusion identified are shown. R209C, R243C, and Q307R mutations in a patient with E/R fusion ALL, A166T mutation in a patient with non-E/R fusion ALL, T329M mutation in a patient with acute leukemia of ambiguous lineage, K317K mutation in a patient with AML, G184S and G203R mutation in patients with early infantile epileptic encephalopathy,15,16 R243H mutation in a patient with breast cancer,20 and Q205L mutation with NIH-3T3 transformation 18. (B) Allele frequency analysis of new GNAO1 mutations by deep genomic sequencing in the specimens identified, corresponding to supplemental Table2.…”

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confidence: 99%

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Identification of functional cooperative mutations of GNAO1 in human acute lymphoblastic leukemia

Song

Yang

et al. 2021

Blood

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Leukemogenesis is characterized by chromosomal rearrangements with additional molecular disruptions, yet the cooperative mechanisms are still unclear. Using whole-exome sequencing of a pair of monozygotic twins discordant for childhood acute lymphoblastic leukemia (ALL) with ETV6-RUNX1 (E/R) gene fusion successively after birth, we identified the R209C mutation of G protein subunit alpha o1 (GNAO1) as a new ALL risk loci. Moreover, GNAO1 missense mutations are only recurrent in ALL patients and are associated with E/R fusion. Ectopic expression of the GNAO1 R209C mutant increased its GTPase activity and promoted cell proliferation and cell neoplastic transformation. Combined with the E/R fusion, the GNAO1 R209C mutant promoted leukemogenesis through activating PI3K/Akt/mTOR signaling. Reciprocally, activated mTORC1 phosphorylated p300 acetyltransferase, which acetylated E/R and thereby enhanced the E/R transcriptional activity of GNAO1 R209C. Thus, our study provides clinical evidence for the functional cooperation of GNAO1 mutants and E/R fusion, suggesting GNAO1 as a potential therapeutic target in human leukemia.

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Section: Discussionmentioning

confidence: 99%

Section: Gnao1 Missense Mutations In Patients With Allmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of functional cooperative mutations of GNAO1 in human acute lymphoblastic leukemia

Song

Yang

et al. 2021

Blood

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“…The functions of G␣ 12 and G␣ 13 have not been clearly defined. Overexpression of activated forms of these proteins transforms fibroblasts (312). Expression and activation of G␣ 12 and G␣ 13 occurs in differentiation of P19 embryonic stem cells in response to retinoic acid (264).…”

Section: ␣-Subunitsmentioning

confidence: 99%

Physiological Regulation of G Protein-Linked Signaling

Morris

Malbon

1999

Physiological Reviews

401

294

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Heterotrimeric G proteins in vertebrates constitute a family molecular switches that transduce the activation of a populous group of cell-surface receptors to a group of diverse effector units. The receptors include the photopigments such as rhodopsin and prominent families such as the adrenergic, muscarinic acetylcholine, and chemokine receptors involved in regulating a broad spectrum of responses in humans. Signals from receptors are sensed by heterotrimeric G proteins and transduced to effectors such as adenylyl cyclases, phospholipases, and various ion channels. Physiological regulation of G protein-linked receptors allows for integration of signals that directly or indirectly effect the signaling from receptor-->G protein-->effector(s). Steroid hormones can regulate signaling via transcriptional control of the activities of the genes encoding members of G protein-linked pathways. Posttranscriptional mechanisms are under physiological control, altering the stability of preexisting mRNA and affording an additional level for regulation. Protein phosphorylation, protein prenylation, and proteolysis constitute major posttranslational mechanisms employed in the physiological regulation of G protein-linked signaling. Drawing upon mechanisms at all three levels, physiological regulation permits integration of demands placed on G protein-linked signaling.

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G Proteins in Signal Transduction

Birnbaumer

1995

Biomembranes

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The Q205LGo-alpha subunit expressed in NIH-3T3 cells induces transformation

Cited by 55 publications

References 27 publications

Identification of functional cooperative mutations of GNAO1 in human acute lymphoblastic leukemia

Identification of functional cooperative mutations of GNAO1 in human acute lymphoblastic leukemia

Physiological Regulation of G Protein-Linked Signaling

G Proteins in Signal Transduction

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