Charles J Sherr

..Studies of a knock-in mouse strain in which sequences encoding green fluorescent protein were substituted for those encoding p19Arf argue that the Arf gene responds to latent oncogenic signals in vivo to eliminate incipient cancer cells...

..Their study has become a centerpiece of contemporary cancer research...

..Nucleolar relocalization of Mdm2 by ARF connotes a novel mechanism for preventing p53 turnover and provides a framework for understanding how stress signals cooperate to regulate p53 function...

..Like the tumor suppressor protein p53, components of this "RB pathway," although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life...

..However, ARF has been reported to physically associate with proteins other than MDM2 and to have p53-independent activities, most of which remain controversial and poorly understood...

..A complex signalling network that interconnects the activities of RB and p53 monitors oncogenic stimuli to provide a cell-autonomous mode of tumour surveillance...

..Pinpointing the various ways by which the functions of RB and p53 are subverted in individual tumors should provide a rational basis for developing more refined tumor-specific therapies...

..Lesions in the p16--cyclin D-CDK4--Rb and ARF--Mdm2--p53 pathways occur so frequently in cancer, regardless of patient age or tumor type, that they appear to be part of the life history of most, if not all, cancer cells...

..Thus, none of these genes is strictly essential for cell cycle progression. To what extent is the prevailing dogma incorrect, and how can the recent findings be reconciled with past work?..

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..Although it has been generally assumed that p18(Ink4c) and p19(Ink4d) are biochemically similar Cdk inhibitors, the major differences in their stability and turnover are likely key to understanding their distinct biological functions...

..These results underscore the functional interplay between a network of specific genes that recurrently contribute to medulloblastoma formation...

..Therefore, by targeting multiple genes regulating the differentiation state of GNPs, Atoh1 collaborates with the pro-proliferative Gli1-dependent transcriptional program to influence medulloblastoma development...

..Hence, salutary cytokines in the hematopoietic microenvironment can facilitate leukemic proliferation and confer resistance to targeted therapy...

..In this respect, this mouse medulloblastoma model recapitulates the vast majority of human medulloblastomas that do not sustain TP53 mutations and are not aneuploid...

..Re-engineering of the p19Arf N terminus to provide consensus sequences for N-acetylation limited Arf ubiquitination and decelerated its turnover...

..Therefore, Myc does not require E2f1 to induce Arf, p53, or apoptosis in B cells, but depends upon E2f1 to accelerate cell cycle progression and downregulate p27(Kip1)...

..Reduction of Ubc9 levels with short hairpin RNAs rendered similar results. We suggest that Arf's p53-independent effects on gene expression and tumor suppression might depend on Arf-induced sumoylation...

..These results provide definitive genetic evidence that expression of N-Myc and concomitant down-regulation of Ink4c and Kip1 contribute to the proper development of the cerebellum...

..Evolution may have linked a primordial nucleolar Arf function to Mdm2 and p53, creating a more efficient checkpoint-signaling pathway for coordinating ribosomal biogenesis and cell cycle progression...

..Hence, IL-7 can reduce the sensitivity of Bcr-Abl+ pre-B cells to imatinib. Selective inhibitors of both Bcr-Abl and the IL-7 transducing JAK kinases may therefore prove beneficial in treating Ph+ ALL...

..Inactivation of Arf in this manner led to the outgrowth of tumor cells expressing GFP, thereby providing direct evidence that the Arf promoter monitors latent oncogenic signals in vivo...

..We infer that very low levels of Arf are tumor suppressive, and that further induction provides the selective pressure for the emergence of tumors that have inactivated the gene...

..Thus, ubiquitination and sumoylation can each influence Arf tumor suppressor activity...

..We favor the idea that NPMc also contributes to AML by dominantly perturbing other functions of the wild type NPM protein...

..Crossing the Arf(Cre/FL) alleles onto a Pdgfrbeta(FL/FL) background normalized all histopathology and restored vision fully...

..Methylation of the INK4C (CDKN2C) promoter and complete loss of p18(INK4C) protein expression were detected in a significant fraction of human MBs again pointing toward a role for INK4C in suppression of MB formation...

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..Together, the results indicate that p19(Arf) induces a broad spectrum of proteins that likely act in concert to arrest cell proliferation...

..Arf activation by ICN1 in T cells thereby provides stage-specific tumor suppression but also a strong selective pressure for deletion of the locus in T-ALL...

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..An NPM mutant lacking its carboxyl-terminal nucleic acid-binding domain oligomerizes with endogenous NPM, inhibits p19(Arf) from entering into 2- to 5-MDa particles, and overrides the ability of p19(Arf) to retard rRNA processing...

..A recent study reveals a novel level of feedback control, whereby induced p19(Arf) binds to Myc and blocks cell proliferation by selectively impairing its transactivation functions...

..Methylation of INK4C (CDKN2C) was observed in four of 23 human MBs, and p18(INK4C) protein expression was extinguished in 14 of 73 cases. Hence, p18(INK4C) loss may contribute to MB formation in children...

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..Notch mutation and Arf inactivation appear to independently cooperate in no requisite order with Lmo2 overexpression in inducing T-ALL, and all 3 events remained insufficient to guarantee immediate tumor development...

..Thus, two p53-inducible gene products, Hzf and p21Cip1, act concomitantly to enforce the G(2) checkpoint...

..Why is this the case, and how do these genetic lesions contribute to an aggressive disease that fails to durably respond to targeted kinase inhibitors?..

..This indicates that these antibodies should be useful in detecting the endogenous p(19Arf) protein at specific stages of mouse development and during early stages of tumorigenesis...

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..Inhibition of the retinoblastoma protein had no effect on the ability of ARF to arrest TKO MEFs. Thus, in the absence of Mdm2, p19(ARF) interacts with other targets to inhibit cell proliferation...

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..In this setting, reintroduction of p19(ARF) restores p53's ability to induce p21(Cip1) and mdm2, implying that, in addition to stabilizing p53, ARF modulates p53-dependent function through an additional mechanism...

..Therefore, cancer-associated mutations within exon 2 of the INK4a gene specifically target p16INK4a, and not p19ARF, for inactivation...

..Further study will be needed to determine whether gene-specific mutations implicate hDMP1 as a tumor suppressor in acute leukemias with deletions of the long arm of chromosome 7 or in other types of human malignancy...

..Our data indicate that p18(Ink4c) and p19(Ink4d) are essential for male fertility. These two Cdk inhibitors collaborate in regulating spermatogenesis, helping to ensure mitotic exit and the normal meiotic maturation of spermatocytes...

..Hence, the ARF-Mdm2 interaction can be viewed as bidirectional, with each protein being capable of regulating the subnuclear localization of the other...

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..Economical reutilization of coding sequences in this manner is practically without precedent in mammalian genomes, and the unitary inheritance of p16INK4a and p19ARF may underlie their dual requirement in cell cycle control...

..Thus, cyclin D1, and most likely D2, are rate limiting for G1 progression...

..Thus, p34PSK-J3 is a cyclin D-regulated catalytic subunit that acts as an Rb (but not H1) kinase...

..The longer latency of tumor formation in ARF-null versus p53-null mice, therefore, appears to enable a broader spectrum of tumors to emerge...

..Therefore, whereas ARF and Atm signal to p53 through distinct pathways, the loss of ARF can modify p53-dependent features of the Atm-null phenotype...

..Therefore, Myc activation strongly selects for spontaneous inactivation of the ARF-Mdm2-p53 pathway in vivo, cancelling its protective checkpoint function and accelerating progression to malignancy...

..However, introduction of a vector encoding p19 into mouse NIH 3T3 cells leads to constitutive p19 synthesis, inhibits cyclin D1-CDK4 activity in vivo, and induces G1 phase arrest...

..These results raise the possibility that cyclin D-dependent kinases regulate gene expression in an RB independent manner, thereby serving to link other genetic programs to the cell cycle clock...

..The D-type cyclins may play dual roles as cdk4 regulatory subunits and as adaptor proteins that physically target active enzyme complexes to particular substrates...

..However, such interactions do not inhibit Mdm2 E3 ubiquitin ligase activity in vitro using p53 as a substrate. Expression of growth-inhibitory Mdm2 isoforms in tumors remains an enigma...

..Therefore, INK4a encodes growth inhibitory proteins that act upstream of the retinoblastoma protein and p53. Mutations and deletions targeting this locus in cancer cells are unlikely to be functionally equivalent...

..Therefore, p19INK4d may contribute to maintaining the quiescent state, acting as a buffer to prevent reactivation of cyclin D-dependent kinases in terminally differentiated cells...

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..In the absence of both CKIs, the severe reduction in cyclin D-dependent kinase activity was well tolerated and had no overt effects on the cell cycle...

..The timing of p36CYL expression, its rapid turnover in the absence of CSF-1, and its phosphorylation and transient binding to a cdc2-related polypeptide suggest that CYL genes may function during S phase commitment...

..Therefore, apart from its recently recognized role in protecting cells from potentially oncogenic signals, ARF can be induced in response to antiproliferative stimuli that do not obligatorily lead to apoptosis...

..Expression vectors encoding human or mouse p16INK4a caused G1 phase arrest in NIH3T3 fibroblasts, and cyclin D1- and cdk4-dependent pRb kinase activities were inhibited in the p16INK4a-arrested cells...

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..Could this account for the Mdm2- and p53-independent tumor suppressive effects of ARF?..

..Thus, constitutive activation of the CSF-1 receptor gene, either by mutation or gene rearrangement, might be expected to contribute to leukemia...

..The complex patterns of expression of individual cyclin D genes and their evolutionary conservation across species suggest that each family member may play a distinct role in cell cycle progression...

..The results confirm that C-terminal truncation of the c-fms gene is insufficient to activate its transforming potential and suggest that an additional mutation in its distal extracellular domain is required for oncogenic activation...

..The absence of tumors in INK4d-deficient animals demonstrates that, unlike INK4a, INK4d is not a tumor suppressor but is instead involved in spermatogenesis...

..Therefore, p19(Ink4d) and p27(Kip1) cooperate to maintain differentiated neurons in a quiescent state that is potentially reversible...

..At face value, these results are inconsistent with the hypothesis that cdc25A acts directly on cdk2 to activate its S phase promoting function...

..Targets of the delayed-early response include novel cyclin genes that may play a role in S phase commitment...

..Therefore, phosphorylation and proteolytic turnover of cyclin D1 and its subcellular localization during the cell division cycle are linked through the action of GSK-3beta...

..The study of CSF-1 and its receptor should provide information concerning the role of tyrosine kinases in regulating the normal growth and differentiation of haematopoietic cells and in contributing to their malignant transformation...

..Therefore, critical mutations in the c-fms gene or overexpression of CSF-1R in immature myeloid precursors might each contribute to leukaemia...

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..Although expression of the c-fms product (CSF-1 receptor) is normally restricted to cells of the mononuclear phagocyte series, the v-fms-coded glycoprotein can contribute to proliferative abnormalities of multiple hematopoietic lineages...

..The ability of v-fms to induce transformation of early pre-B cells in vitro underscores the capacity of oncogenic mutants of the colony-stimulating factor-1 receptor to function outside the mononuclear phagocyte lineage...

..Although p53 mutations or Arf deletion normally occur in approximately 50% of E(mu)-Myc-induced lymphomas, Dmp1 loss obviates selection for such mutations, indicating that Dmp1 is a potent genetic modifier of the Arf-p53 pathway in vivo...

..The genetic alterations in the c-fms gene that unmask its latent transforming potential abrogate its lineage-specific activity and enable v-fms to transform a variety of cells that do not normally express CSF-1 receptors...

..Together, these data suggest that ARF function is compromised, but not eliminated, in animals lacking functional DMP1...

..Therefore, whereas Arf loss alone appears to be the major determinant of establishment of murine fibroblast and preB cell lines in culture, p16(Ink4a) provides an effective barrier to immortalization of bone marrow-derived macrophages...

..Whereas p18INK4c and p19INK4d may regulate pre- and postnatal development, p16INK4a more likely plays a checkpoint function during cell senescence that underscores its selective role as a tumor suppressor...

..The ability of v-fms to transform hematopoietic target cells suggests that critical alterations in the c-fms proto-oncogene might similarly contribute to leukemia...

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..These antibodies should prove useful not only for identifying and quantitating CSF-1R on receptor-bearing cells but for abrogating specific receptor signals that govern the proliferation and survival of human mononuclear phagocytes...

..Thus, although the PDGF and CSF-1 receptors are structurally related and appear to be derived from a single ancestor gene, only PDGF-induced mitogenesis in fibroblasts correlated with tyrosine phosphorylation of PLC-gamma...

..These data indicate that two different Myb family proteins collaborate in regulating APN gene expression and point to a role for DMP1 in normal myeloid cell development...

..We speculate that transcriptional down-regulation in response to Arf-induced sumoylation may account for Arf's p53-independent functions...

..By contrast, the mature cell surface glycoprotein encoded by the v-fms oncogene was phosphorylated on tyrosine in the absence of CSF-1, suggesting that it functions as a ligand-independent kinase...

..Thus, complete oncogenic activation of the c-fms gene appears to require two events: one which alters a putative negative regulatory site of tyrosine phosphorylation, and a second which phenocopies a ligand-induced conformational change...

..The as yet unidentified c-fms promoter/enhancer sequences may be confined to the nucleotides separating the two genes or could potentially lie within the PDGF receptor gene itself...

..Our data indicate the presence of the novel Jun-Dmp1 pathway that directly links oncogenic Ras-Raf signaling and p19(Arf), independent of the classical cyclin D1/Cdk4-Rb-E2F pathway...

..Recent evidence emerging from mouse tumor models distinguishes the activities of p16(Ink4a) and p19(Arf) in regulating tumor onset and identifies differences in their responsiveness to drugs...

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