The transcription factor B-Myb is essential for S-phase progression and genomic stability in diploid and polyploid megakaryocytes

García, Paloma; Frampton, Jon

doi:10.1242/jcs.02870

Cited by 32 publications

(31 citation statements)

References 55 publications

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“…B-Myb transactivates genes required for the G 2 /M cell cycle transition by forming the dREAM/Myb-MuvB-like complex, which was originally identified in Drosophila (23,(44)(45)(46)(47). Furthermore, mutation or downregulation of B-Myb results in genome instability (27,48,49). In contrast, pVHL induces cell cycle arrest at the G 0 /G 1 phase (50), and knockdown of HIF-2␣ is sufficient to suppress aneuploidy (50).…”

Section: Resultsmentioning

confidence: 99%

Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α

Okumura

Uematsu

Byrne

et al. 2016

Molecular and Cellular Biology

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U biquitin-mediated proteolysis by the 26S proteasome plays an important role in the elimination of short-lived proteins (1), including those involved in cell cycle progression, cellular signaling in response to environmental stress or extracellular ligands, morphogenesis, secretion, DNA repair, and organelle biogenesis (2, 3). The pathway consists of two key steps, namely, the covalent attachment of multiple ubiquitin molecules to a target protein and the degradation of the ubiquitinated protein by the 26S proteasome complex. Several components act in concert to attach ubiquitin to a target protein, including a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-protein isopeptide ligase (E3). E3 is directly responsible for substrate recognition. On the basis of structural similarity, E3 enzymes are classified into three families: the HECT (homologous to E6-AP COOH terminus) family, the U-box family, and the RING finger-containing protein family.The elongin B and C-Cul2 or Cul5-SOCS box protein (ECS) family belongs to the cullin RING ligase (CRL) superfamily (4). pVHL, the protein product of the von Hippel-Lindau (VHL) tumor suppressor gene, is a member of the ECS family. pVHL forms a complex with elongins B and C, Cul2, and the RING finger protein Rbx1 (5, 6). The CRL2 pVHL complex has ubiquitin ligase activity and targets the hypoxia-inducible factor ␣ (HIF-␣) family of transcription factors (HIF-1 to -3␣) for proteasomal degradation (7). At normal oxygen levels, proline residues in the LXXLAP sequence motif of HIF-␣ proteins are hydroxylated by three prolyl hydroxylases (PHD1 to -3), and an in-depth study revealed that PHD2 is a critical enzyme for the hydroxylation of HIF-1␣ (8, 9). Hydroxylated HIF-␣ is targeted by pVHL for polyubiquitination and proteasomal degradation (10-12). Under conditions of hypoxia (low oxygen level), HIF-␣ is not hydroxylated by PHDs and is therefore not recognized or targeted for degradation by pVHL. The unhydroxylated HIF-␣ dimerizes with constitutively expressed HIF-1␤, also known as an aryl hydrocarbon receptor nuclear translocator (ARNT), and translocates to the nucleus, where it induces the transcription of downstream target genes, including the genes coding for vascular endothelial growth factor A (VEGFA), solute carrier family 2 member 1 (SLC2A1; also known as GLUT1), and platelet-derived growth factor (PDGF) (13). Loss of functional pVHL protein prevents the O 2 -dependent degradation of HIF-␣, resulting in constitutive expression of HIF-dependent genes and VHL disease, which is characterized by a variety of lesions, including hemangioblastomas, renal clear cell carcinomas, pheochromocytomas, pancreatic islet cell tumors, endolymphatic sac tumors, and papillary cystadenomas of the broad ligament (females) and epididymis (males) (13).Studies showing that heterozygous pVHL ϩ/Ϫ mice are phenotypically normal and VHL Ϫ/Ϫ mice die at embryonic day 10.5 (E10.5) to E12.5 (14), together with the existence of many pVHLinteracting proteins (13), a...

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Section: Resultsmentioning

confidence: 99%

Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α

Okumura

Uematsu

Byrne

et al. 2016

Molecular and Cellular Biology

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“…Aberrant B-MYB expression or amplification has been documented in different types of human cancers, suggesting a role in tumorigenesis [33][34][35]. Furthermore B-MYB was recently implicated in the maintenance of pluripotency, chromatin stability and normal cell cycle progression [36][37][38].…”

Section: Discussionmentioning

confidence: 99%

Addiction of MYCN Amplified Tumours to B-MYB Underscores a Reciprocal Regulatory Loop

Gualdrini¹,

Corvetta²,

Cantilena³

et al. 2010

Oncotarget

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“…Therefore, the repression of either DEK or B-MYB is sufficient to induce senescence. Previous studies reported that B-MYB or DEK repression can inhibit cell growth or survival, but did not explicitly demonstrate the acquisition of senescence markers (2,31,71,75,89). We also determined whether repression of DEK or B-MYB was required for senescence in E6 cells.…”

Section: Downloaded Frommentioning

confidence: 91%

Human Papillomavirus E7 Repression in Cervical Carcinoma Cells Initiates a Transcriptional Cascade Driven by the Retinoblastoma Family, Resulting in Senescence

Johung

Goodwin²,

DiMaio

2007

J Virol

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Replicative senescence, an irreversible growth-arrested state attained by primary somatic cells after extensive passage in culture, reflects an important tumor suppressor mechanism in vivo and is a model for various aspects of cellular and organismal aging (10,13,16,76). Senescence is characterized by a constellation of features including irreversible growth arrest, elevated senescence-associated ␤-galactosidase (SA␤-gal) activity, and increased autofluorescence, cell size, and cellular granularity. Although the p53 and retinoblastoma (Rb) tumor suppressor pathways appear to be important mediators of replicative senescence (37,77), it has been difficult to characterize the genetic and biochemical basis of replicative senescence because it is a heterogeneous process that occurs after months in cell culture. Senescence-like states can also be acutely induced by oxidative stress, introduction of an activated ras oncogene or tumor suppressor genes, or various other treatments (reviewed in reference 78). The rapid induction of senescence by these diverse stimuli implies that senescence is a genetically programmed cellular process analogous to cell cycle progression or apoptosis.We and others have described a model of induced senescence in cervical cancer cells (36,57,88). Cervical carcinogenesis is initiated by persistent infection of cervical keratinocytes with a high-risk human papillomavirus (HPV), such as HPV16 or HPV18. Cervical carcinoma cells continuously express the HPV E6 and E7 oncogenes, resulting in sustained inactivation of the p53 and Rb pathways, respectively (54, 58). Repression of the E6 and E7 genes in cervical carcinoma cell lines such as HeLa cells by expression of the bovine papillomavirus (BPV) E2 transcriptional repressor reactivates the endogenous p53 and Rb pathways and induces a robust senescence response that proceeds rapidly and synchronously and becomes irreversible by 5 days after E2 expression (20,24,36,41,42,45,57,88). Constitutive expression of the HPV16 E6 and E7 genes in HeLa cells can prevent BPV E2-induced senescence, demonstrating that HPV repression is required for this response (18,27,33,34,36,45,63,64,68). In contrast, high-level expression of HPV E2 proteins can result in cellular effects independently of E6/E7 repression (9,19,28,66,84).To initiate a genetic dissection of the pathways leading to senescence in response to HPV repression, we engineered HeLa cells to constitutively express an exogenous HPV16 E6 gene (18). Repression of the endogenous HPV18 E7 gene in these cells by E2 expression activates the Rb but not the p53 pathway, which remains dormant because of enforced expression of HPV16 E6. Nevertheless, E7 repression efficiently induces senescence in these cells, demonstrating that p53 induction is not required for senescence (18). Genetic studies strongly suggest that this induced senescence response requires activation of the Rb family (63,70,88). In addition, inactivation of the Rb pathway in primary keratinocytes is required to bypass replicative senescence (22,...

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The transcription factor B-Myb is essential for S-phase progression and genomic stability in diploid and polyploid megakaryocytes

Cited by 32 publications

References 55 publications

Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α

Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α

Addiction of MYCN Amplified Tumours to B-MYB Underscores a Reciprocal Regulatory Loop

Human Papillomavirus E7 Repression in Cervical Carcinoma Cells Initiates a Transcriptional Cascade Driven by the Retinoblastoma Family, Resulting in Senescence

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