X-linked thrombocytopenia caused by a novel mutation ofGATA-1

Mehaffey, Michele G.; Newton, Anthea L.; Gandhi, Manish J.; Crossley, Merlin; Drachman, Jonathan G.

doi:10.1182/blood.v98.9.2681

Cited by 183 publications

(154 citation statements)

References 25 publications

Supporting

Mentioning

149

Contrasting

Unclassified

Order By: Relevance

“…52 In particular, patients with the G208S alteration in GATA-1 accumulate large, immature megakaryocytes within their bone marrow and suffer from macrothrombocytopenia. 53 Similarly, expression of the V205G mutant of GATA-1 in place of the wild-type protein also leads to the generation of large, abnormal megakaryocytes both in vivo and in vitro. 20,54 As shown in this report, these latter mutant megakaryocytes express cyclin D1 at more than 20 times the amount found in GATA-1-deficient counterparts.…”

Section: Human Gata1 Mutations Have Differential Effects On Megakaryomentioning

confidence: 99%

Cyclin D–Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization

Muntean

Pang

Poncz

et al. 2007

Blood

View full text Add to dashboard Cite

Endomitosis is a unique form of cell cycle used by megakaryocytes, in which the latter stages of mitosis are bypassed so that the cell can increase its DNA content and size. Although several transcription factors, including GATA-1 and RUNX-1, have been implicated in this process, the link between transcription factors and polyploidization remains undefined. Here we show that GATA-1-deficient megakaryocytes, which display reduced size and polyploidization, express nearly 10-fold less cyclin D1 and 10-fold increased levels of p16 compared with their wild-type counterparts. We further demonstrate that cyclin D1 is a direct GATA-1 target in megakaryocytes, but not erythroid cells. Restoration of cyclin D1 expression, when accompanied by ectopic overexpression of its partner Cdk4, resulted in a dramatic increase in megakaryocyte size and DNA content. However, terminal differentiation was not rescued. Of note, polyploidization was only modestly reduced in cyclin D1-deficient mice, likely due to compensa- IntroductionCyclin D1 is one of a battery of cell-cycle regulatory proteins, including cyclins, cyclin-dependent kinases (Cdks), and Cdk inhibitors, that is required for proper regulation of cell cycle and cell differentiation. 1 G 1 -specific cyclin-Cdk complexes, including the D-type cyclins and Cdk4/6, promote progression into S phase through the phosphorylation and inhibition of pocket proteins (pRb, p107, and p130). 2 Hypophosphorylated pocket proteins bind and inhibit the E2F family of transcription factors that control genes involved in proliferation and DNA replication, including cyclin E. 3 Phosphorylation of pocket proteins by cyclin D1-Cdk4/6 causes their dissociation from E2F proteins, leading to transcriptional activation and a commitment to cell-cycle progression. 4 However, recent data have described a more intricate balance between different phosphorylation states and function of pRb. Ezhevsky et al have shown that cyclin D-Cdk4/6 hypophosphorylates pRb in early G 1 , activating pRb as a transcriptional repressor and allowing it to bind E2F and E1A proteins. 5 In late G 1 , cyclin E-Cdk2 complexes hyperphosphorylate pRb, thereby inactivating it and allowing for progression into S phase. These findings lend credence to the model that cyclin D and cyclin E activities are not equivalent. Of note, cellular proliferation is not affected when individual D-type cyclins or Cdk4 or Cdk6 are disrupted in mice, although individual knockout lines display specific growth defects. For example, cyclin D1-deficient animals are smaller than their littermates and show hypoplasia of the retina and mammary epithelium. [6][7][8][9] Most tissues express multiple D-type cyclins, however, which allows for compensation when one is knocked out.Notably, mice that are deficient for all 3 D-type cyclins show gross defects in multiple cell types, including hematopoietic progenitors. 10 Cdk inhibitors offer another means of regulating cell-cycle progression. For example, p16 ink4A (p16), a member of the INK4 family of cell-cycle in...

show abstract

Section: Human Gata1 Mutations Have Differential Effects On Megakaryomentioning

confidence: 99%

Cyclin D–Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization

Muntean

Pang

Poncz

et al. 2007

Blood

View full text Add to dashboard Cite

show abstract

“…Vertebrate GATA-1 and Runx1 are coexpressed and have overlapping functions during hematopoiesis, including megakaryopoiesis (15)(16)(17)(18)(19)(20)(21)(22). In addition, in vitro studies have suggested that the GATA-1:Runx1 complex directs megakaryocyte differentiation (22).…”

Section: Srp and Lz Synergistically Activate The Crystal Cell Programmentioning

confidence: 99%

Combinatorial interactions of Serpent, Lozenge, and U-shaped regulate crystal cell lineage commitment during Drosophila hematopoiesis

Fossett

Hyman

Gajewski

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

120

View full text Add to dashboard Cite

The GATA factor Serpent (Srp) is required for hemocyte precursor formation during Drosophila hematopoiesis. These blood cell progenitors give rise to two distinct lineages within the developing embryo. Lozenge, a Runx protein homologue, and Glial cells missing-1 and -2 are essential for crystal cell and plasmatocyte production, respectively. In contrast U-shaped, a Friend of GATA class factor, antagonizes crystal cell formation. Here we show that Srp, Lozenge, and U-shaped interact in different combinations to regulate crystal cell lineage commitment. Coexpression of Srp and Lozenge synergistically activated the crystal cell program in both embryonic and larval stages. Furthermore, expression of Lozenge and SrpNC, a Srp isoform with N-and C-terminal zinc fingers, inhibited u-shaped expression, indicating that crystal cell activation coincided with the down-regulation of this repressor-encoding gene. In contrast, whereas U-shaped and SrpNC together blocked crystal cell production, coexpression of U-shaped with noninteracting Srp proteins failed to prevent overproduction of this hemocyte population. Such results indicated that U-shaped and SrpNC must interact to block crystal cell production. Taken together, these studies show that the specialized SrpNC isoform plays a pivotal role during crystal cell lineage commitment, acting as an activator or repressor depending on the availability of specific transcriptional coregulators. These findings provide definitive proof of the combinatorial regulation of hematopoiesis in Drosophila and an in vivo demonstration of GATA and Runx functional interaction in a blood cell commitment program.

show abstract

“…For instance, somatic mutations in the GATA1 gene, which result in the production of GATA1-⌬NT (or GATA1s), are a prerequisite for the onset of transient myeloproliferative disorder (TMD) and subsequent acute megakaryoblastic leukemia (AMkL) in Down syndrome patients (44). Similarly, GATA1 mutations in the N-finger domain were found in multiple cases with familial anemia and thrombocytopenia (45)(46)(47)(48). In the latter cases, the association potential of GATA1 with either FOG1 or GATAbox DNA was attenuated, indicating that the N-finger domain is important for the GATA1 activity.…”

Section: Discussionmentioning

confidence: 99%

N- and C-terminal Transactivation Domains of GATA1 Protein Coordinate Hematopoietic Program

Kaneko

Kobayashi

Yamamoto

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The N-terminal transactivation domain (N-TAD) is requisite for GATA1 function in vivo. Results: The C-terminal region of GATA1 works as TAD, and fetal hematopoiesis is perturbed in the GATA1-deficient mice rescued with GATA1 lacking C-terminal TAD activity. Conclusion: GATA1 has two TADs, which differentially work. Significance: The complex nature of molecular mechanisms is underlying how GATA1 works for the maintenance of hematopoietic homeostasis.

show abstract

X-linked thrombocytopenia caused by a novel mutation ofGATA-1

Cited by 183 publications

References 25 publications

Cyclin D–Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization

Cyclin D–Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization

Combinatorial interactions of Serpent, Lozenge, and U-shaped regulate crystal cell lineage commitment during Drosophila hematopoiesis

N- and C-terminal Transactivation Domains of GATA1 Protein Coordinate Hematopoietic Program

Contact Info

Product

Resources

About