Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia

Rane, Sushil G.; Dubus, Pierre; Mettus, Richard V.; Galbreath, Elizabeth; Boden, Guenther; Reddy, E. Premkumar; Barbacid, Mariano

doi:10.1038/8751

Cited by 678 publications

(735 citation statements)

References 37 publications

Supporting

Mentioning

687

Contrasting

Unclassified

Order By: Relevance

“…Second, our data shed new light on the puzzling issue of redundancy within the INK4 family of Cdk inhibitors (Ruas and Peters, 1998;Sherr and Roberts, 1999), in particular the question why p19 INK4d which shares its biochemical properties with the closely related p16 INK4a tumour suppressor, is apparently not targeted by mutations in cancer. Thus, while both Cdk4 (Rane et al, 1999), the major target of all INK4 family members (Sherr and Roberts, 1999), and p19 INK4d (Zindy et al, 2000) appear essential for proper development and function of the testis, the lack of the p19 INK4d gene in the mouse does not result in an increased incidence of testicular tumours (Zindy et al, 2000). Taken together with our present data, we propose that the answer to this puzzle may lie in a tight regulation of expression of p19 INK4d during development.…”

Section: Resultsmentioning

confidence: 47%

“…The fact that a marked testicular atrophy was the only obvious phenotype of mice de®cient in p19 INK4d (Zindy et al, 2000), in contrast to apparently normal testes in mice genetically deprived of the INK4a locus (Serrano et al, 1996), suggested a speci®c role of p19 INK4d in mouse spermatogenesis. Marked testicular defects in mice devoid of Cdk4 (Rane et al, 1999) or cyclin D2 (Sicinski et al, 1996) further suggested a critical role of cyclin D-dependent kinases and their regulators in testis biology. While searching for potential aberrations of p19 INK4d in testicular tumours, we were also hoping to address the puzzling discrepancy between the apparently indistinguishable biochemical properties of all INK4 family members including the p16 INK4a tumour suppressor and the fact that p19 INK4d appears to be neither deleted nor mutated in tumours (Ruas and Peters, 1998).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

et al. 2000

View full text Add to dashboard Cite

p19 INK4d , a member of the INK4 family of cyclindependent kinase inhibitors, negatively regulates the proto-oncogenic cyclin D/CDK4(6) complexes whose ability to phosphorylate the retinoblastoma tumour suppressor (RB) promotes G1/S transition. In contrast to the related p16 INK4a tumour suppressor, expression patterns of 19 INK4d in human tissues and tumours remain unknown. As the RB pathway is commonly targeted in cancer, and mouse models suggest a role for p19 INK4d in spermatogenesis, we examined the abundance and localization of p19 INK4d in the human testis, both during normal development and at various stages of germ-cell tumour pathogenesis. Our data show that the p19 INK4d protein is abundant in spermatocytes of normal human adult testes, whereas virtually no p19 INK4d is detectable in testicular cancer, including the preinvasive carcinoma in situ stage. Together with the lack of p19 INK4d in human foetal germ cells, these results support the concept of foetal origin of the testicular germ-cell tumours, and help better understand the emerging role of the RB pathway in spermatogenesis and tumorigenesis in the human testis. Oncogene (2000) 19, 4146 ± 4150.

show abstract

Section: Resultsmentioning

confidence: 47%

Section: Introductionmentioning

confidence: 99%

Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

et al. 2000

View full text Add to dashboard Cite

show abstract

“…In addition, Cdk4 is dispensable for liver regeneration following partial hepatectomy [64], an assay considered to be one of the most stringent to evaluate the proliferative capacity of an adult tissue [65]. Altogether, these data support that Cdk4 is, with the exception of certain cell types [9,19,66,67], overall dispensable for adult tissue homeostasis.…”

Section: Discussionmentioning

confidence: 71%

“…As most Cdk4 À/À mice survive until adulthood [9,19] and Cdk6 À/À develop normally [10], we took advantage of these genetic models to examine the contribution of Cdk4/6 to adult NPC proliferation. In agreement with previous studies reporting the dwarfism-like phenotype of Cdk4-deficient mice [9,19], we first observed that Cdk4 À/À brains were smaller and lighter than their WT counterparts at every postnatal stage analyzed, suggesting an important role for Cdk4 during brain development (Supporting Information Fig. 3).…”

Section: Cdk6 Is Critical For Neural Precursor Proliferation In the Smentioning

confidence: 99%

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

et al. 2011

Self Cite

View full text Add to dashboard Cite

The presence of neurogenic precursors in the adult mammalian brain is now widely accepted, but the mechanisms coupling their proliferation with the onset of neuronal differentiation remain unknown. Here, we unravel the major contribution of the G 1 regulator cyclin-dependent kinase 6 (Cdk6) to adult neurogenesis. We found that Cdk6 was essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Specifically, Cdk6 deficiency prevents the expansion of neuronally committed precursors by lengthening G 1 phase duration, reducing concomitantly the production of newborn neurons. Altogether, our data support G 1 length as an essential regulator of the switch between proliferation and neuronal differentiation in the adult brain and Cdk6 as one intrinsic key molecular regulator of this process. STEM CELLS 2011;29:713-724 Disclosure of potential conflicts of interest is found at the end of this article.

show abstract

“…p16 Ink4a is an inhibitor of cyclin-dependent kinase (Cdk)-4, a regulatory protein implicated in the first steps of cell cycle entry. Breeding c-myc-3 0 RR C57Bl/6 animals in a Cdk4 R24C mutant background (a dominant Cdk4 oncogene resistant to inhibition by p16 Ink4a and other members of the Ink family [29]) resulted in susceptibility to mantle cell lymphoma (Vincent-Fabert et al, submitted). A convincing demonstration of the essential contribution of the 3 0 RR in lymphomagenesis has been produced by transgenic models of B-cell lymphomas with IgH-c-myc translocations [30].…”

Section: C-myc 3 0 Rr and Lymphomagenesismentioning

confidence: 99%

The IgH 3′ regulatory region and its implication in lymphomagenesis

et al. 2010

View full text Add to dashboard Cite

The 3 0 regulatory region (3 0 RR) located downstream of the IgH gene is the master element that controls class switch recombination and sustains high-level transcription at the plasma-cell stage. This latter role suggests that the 3 0 RR may be involved in oncogene deregulation during the frequent IgH translocation events associated with B-cell malignancies. A convincing demonstration of the essential contribution of 3 0 RR in lymphomagenesis has been provided by transgenic animal models. The mouse 3 0 RR shares a strong structural homology with the regulatory regions located downstream of each human Ca gene. Mouse models exploring the role of the 3 0 RR in B-cell physiology and in malignancies should provide useful indications about the pathophysiology of human cell lymphocyte proliferation.Key words: B cells . Cellular proliferation . Oncology IntroductionDuring precursor B-cell differentiation, genes encoding heavy (H) and light chains of an Ig molecule are somatically assembled from germline DNA. This process, named V(D)J recombination, occurs in the bone marrow prior to antigenic challenge. In germinal centers during the antigen-dependent stages, variable (V) regions become the target of somatic hypermutation (SHM) in activated B cells allowing the generation of high-affinity Ig. In mature B cells, class switch recombination (CSR) deletes the constant (C) m region and replaces it with a downstream C H gene. This enables B cells to express various Ig isotypes but still retain antigen specificity. Once activated, B cells differentiate into Ig-secreting plasma cells. During B-cell development all these events (V(D)J recombination, SHM, CSR, Ig synthesis) are coupled with transcriptional accessibility of the IgH loci. IgH transcription is controlled by the functional interactions of multiple promoters, enhancers and insulators spread among the 2.5 megabases of the locus. Among them, the upstream Em enhancer and the 3 0 regulatory region (3 0 RR) stand out as major players. Chromosomal translocations linking oncogenes to these elements are often implicated as the cause of B-cell malignancies. In this brief review of relevant knock-out and transgenic mouse models, we underline how the physiological functions of the IgH 3 0 RR might translate into a critical role in oncogene deregulation during lymphomagenesis.From the El cis-activating element to the 3 0 RR Thirty years ago, Em was the first transcriptional enhancer discovered upstream of the m gene (Fig. 1A) [1][2][3]. Em deletion in mice confirmed its role in controlling access to the locus prior to D-J recombination, but, moreover, showed its dispensability for CSR and SHM [4]. Eventually, several more transcriptional enhancers were identified at the 3 0 end of the locus. hs1,2 was identified 12.5-kb downstream of the mouse Ca (Fig. 1A) 3306Mini-Review differentiation stages, while hs4 is active during the pre-B-cell stage and throughout B-cell development (Fig. 1A) [8,9]. The modest activity of each of the 3 0 RR elements, however, contributes to a synergic...

show abstract

Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia

Cited by 678 publications

References 37 publications

Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

The IgH 3′ regulatory region and its implication in lymphomagenesis

Contact Info

Product

Resources

About