The Zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim

Jurado, Sabine; Gleeson, Kimberly; O’Donnell, Kristy; Izon, David J.; Walkley, Carl R.; Strasser, Andreas; Tarlinton, David M.; Heierhorst, Jörg

doi:10.1084/jem.20120785

Cited by 38 publications

(78 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…62,63 Interestingly, loss of the transcription factor ASCIZ, with consequent reduction in its target dynein light chain 1, which reportedly links BIM to the dynein motor complex, 62 causes abnormal death of B lymphoid cells, and this can be blocked by concomitant loss of BIM. 64 This suggests that this mode of BIM regulation has a critical role in normal physiology.…”

Section: The Bcl-2-regulated Apoptotic Pathwaymentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

View full text Add to dashboard Cite

Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

show abstract

Section: The Bcl-2-regulated Apoptotic Pathwaymentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

View full text Add to dashboard Cite

show abstract

“…ASCIZ focus formation in response to methylating agents depends on DYNLL1 (Jurado et al, 2012a), but it is not known whether this also involves its transcription factor function. The B cell developmental defect of conditional Asciz/Atmin KO mice could not be rescued by deletion of tp53 or complementation with a pre-arranged B cell receptor transgene (Jurado et al, 2012b), supporting a DNA damageindependent mechanism as cause of the B cell deficiency. ASCIZ was earlier reported to be required for ATM protein stability (and thus termed ATMIN) (Kanu and Behrens, 2007), but this was shown to be incorrect in several subsequent studies (Jurado et al, 2010;Loizou et al, 2011;Zhang et al, 2012).…”

Section: Functionmentioning

confidence: 96%

“…An N-ethyl-N-nitrosourea (ENU)-generated mouse mutant, gasping-6, that contains a missense mutations of a Zinc-chelating Cys residue in the third Zinc-finger domain of Asciz/Atmin also dies during late gestation with overall similar phenotypic defects to the Asciz/Atmin null mice, including absent or hypomorphic lungs (Goggolidou et al, 2014). Conditional Asciz/Atmin KO mice generated using B lympoid-specific Cd19-Cre (Loizou et al, 2011) or Mb1-Cre (Jurado et al, 2012b) have reduced peripheral B cell numbers due to increased apoptotic cell death during B cell development in the bone marrow. The most highly downregulated gene in Ascizdeficient cells is the dynein light chain subunit Dynll1 (Jurado et al, 2012a).…”

Section: Functionmentioning

confidence: 99%

“…The ability of ASCIZ to regulate expression of and bind to the DYNLL1-like dynein light chain (called Cutup) is conserved in Drosophila (Zaytseva et al, 2014). The importance of DYNLL1 as an ASCIZ target is highlighted by findings that B cell developmental defects in conditional Mb1-Cre Asciz KO mice can be rescued by ectopic expression of DYNLL1, or simultaneous KO of the pro-apoptotic protein Bim whose activity is inhibited by DYNLL1 (Jurado et al, 2012b). Likewise, in Drosophila, RNAi knockdown of ASCIZ or Cutup lead to similar developmental defects, which in case of dASCIZ RNAi can be rescued by Cutup overexpression (Zaytseva et al, 2014).…”

Section: Functionmentioning

confidence: 99%

“…Note Cd19-Cre conditional Asciz/Atmin deletion has been reported to cause B cell lymphoma in ~40% of mice (whose genetic background was not specified) before 1 year of age (Loizou et al, 2011), but deletion via Mb1-Cre (which is more efficient than Cd19-Cre during early B lympoid stages) in C57BL/6 mice did not lead to B cell lymphoma until at least 2 years of age (Jurado et al, 2012b). Irrespective of genetic background, no lymphomas were observed when Asciz/Atmin was deleted in earlier haematopoietic stem/progenitor cells via Mx1-Cre (Jurado et al, 2012b) or Vav2-Cre (Cremona and Behrens, 2014).…”

Section: B Cell Lymphomamentioning

confidence: 99%

See 2 more Smart Citations

ATMIN (ATM Interactor)

Heierhorst¹

2015

Atlas of Genetics and Cytogenetics in Oncology and Haematology

View full text Add to dashboard Cite

Review on ASCIZ/ATMIN, with data on DNA/RNA, on the protein encoded and where the gene is implicated. Keywords Apoptosis, dynein, DNA damage, transcription factor, lung IdentityOther names: ASCIZ, ZNF822 HGNC (Hugo): ATMIN Location: 16q23.2 Local order: Gene orientation: centromere -5' ASCIZ/ATMIN 3'-telomere. ASCIZ/ATMIN is flanked towards the centromere by CENPN (in the same transcriptional orientiation) and towards the telomere by C16orf46 in opposite transcriptional orientation (NCBI Gene view, gene ID 23300, version 3-Jun-2014). Note: The gene was originally reported to encode an ATM-substrate Chk2-interacting Zinc-finger protein and referred to by the name ASCIZ in NCBI/Genbank, before the official gene name was changed to ATMIN by HGNC. DNA/RNA DescriptionThe human ASCIZ/ATMIN gene contains five exons over 11497 bases. The main transcript results from splicing of exon A, parts of exon C, and exons D and E and gives rise to the "full-length" protein containing 823 amino acids with four Zinc-fingers. Two alternative transcripts -comprising either exon B, part of exon C and exons D and E, or a longer exon C and exons D and E -give rise to a shorter 667-residue protein with only two Zinc-fingers. The mouse ASCIZ gene structure may be simpler with only four exons and single main mRNA encoding an 818-residue protein similar to the human 4-Zinc-finger product. TranscriptionIn Northern and Western blot experiments, the two main isoforms of ASCIZ/ATMIN are expressed at relatively similar levels in a wide range of human tissues and all cancer-derived cell lines tested (McNees et al., 2005). Northern blots of various mouse tissues also indicate relatively similar expression levels in a wide range of organs (Jurado et al., 2010).

show abstract

The Transcription Factor ASCIZ and Its Target DYNLL1 Are Essential for the Development and Expansion of MYC-Driven B Cell Lymphoma

Wong

Jurado

et al. 2016

Cell Reports

Self Cite

View full text Add to dashboard Cite

How MYC promotes the development of cancer remains to be fully understood. Here, we report that the Zn(2+)-finger transcription factor ASCIZ (ATMIN, ZNF822) synergizes with MYC to activate the expression of dynein light chain (DYNLL1, LC8) in the murine Eμ-Myc model of lymphoma. Deletion of Asciz or Dynll1 prevented the abnormal expansion of pre-B cells in pre-cancerous Eμ-Myc mice and potentiated the pro-apoptotic activity of MYC in pre-leukemic immature B cells. Constitutive loss of Asciz or Dynll1 delayed lymphoma development in Eμ-Myc mice, and induced deletion of Asciz in established lymphomas extended the survival of tumor-bearing mice. We propose that ASCIZ-dependent upregulation of DYNLL1 levels is essential for the development and expansion of MYC-driven lymphomas by enabling the survival of pre-neoplastic and malignant cells.

show abstract

The Zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim

Abstract: B cell development requires the Zinc-finger protein and ATM substrate ASCIZ to signal through DYNLL1 and Bim.

Cited by 38 publications

References 44 publications

The BCL-2 protein family, BH3-mimetics and cancer therapy

The BCL-2 protein family, BH3-mimetics and cancer therapy

ATMIN (ATM Interactor)

The Transcription Factor ASCIZ and Its Target DYNLL1 Are Essential for the Development and Expansion of MYC-Driven B Cell Lymphoma

Contact Info

Product

Resources

About