p53-Independent Expression of p21
            <sup>Cip1</sup>
            in Muscle and Other Terminally Differentiating Cells

Parker, Susan; Eichele, Gregor; Zhang, Pumin; Rawls, Alan; Sands, Arthur; Bradley, Allan; Olson, Eric N.; Harper, J. Wade; Elledge, Stephen J.

doi:10.1126/science.7863329

Cited by 982 publications

(668 citation statements)

References 48 publications

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“…Deletion of p21 was not able to substitute for p53 de®ciency in the rescue of the MDM2 null embryonic lethality, described above (Montes de Oca Luna et al, 1997). Moreover, although the p21 CIP1 gene is transcriptionally activated by p53 (el-Deiry et al, 1993), p21 CIP1 is also upregulated during myogenic di erentiation by a p53-independent mechanism thought to involve MyoDmediated transactivation (Parker et al, 1995;Guo et al, 1995;Halevy et al, 1995;Missero et al, 1995). It has also been shown that p21 CIP1 is poorly expressed in RMS cells lines, concomitant with both MyoD and p53 inactivity, and failure to G 1 arrest (Otten et al, 1997).…”

Section: Digging Deeper ± Prb and P53 At The Crossroadsmentioning

confidence: 99%

Rhabdomyosarcoma – working out the pathways

1999

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Rhabdomyosarcomas constitute a collection of childhood malignancies thought to arise as a consequence of regulatory disruption of skeletal muscle progenitor cell growth and di erentiation. Our understanding of the pathogenesis of this neoplasm has recently bene®ted from the study of normal and malignant myogenic cells in vitro, facilitating the identi®cation of diagnostic cytogenetic markers and the elucidation of mechanisms by which myogenesis is regulated. It is now appreciated that the delicate balance between proliferation and di erentiation, mutually exclusive yet intimately associated processes, is normally controlled in large part through the action of a multitude of growth factors, whose signals are interpreted by members of the MyoD family of helix ± loop ± helix proteins, and key regulatory cell cycle factors. The latter have proven to be frequent targets of mutational events that subvert myogenesis and promote the development of rhabdomyosarcoma. Although signi®cant progress has been made in the treatment of rhabdomyosarcoma, patients presenting with metastatic disease or certain high risk features are still faced with a dismal prognosis. Only now are genetically engineered mouse models becoming available that are certain to provide fresh insights into the molecular/genetic pathways by which rhabdomyosarcomas arise and progress, and to suggest novel avenues of therapeutic opportunity.

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Section: Digging Deeper ± Prb and P53 At The Crossroadsmentioning

confidence: 99%

Rhabdomyosarcoma – working out the pathways

1999

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“…The archetypal member of this family, p21, was isolated as a Cdk2-associated protein and an inhibitor of Cdk2 (Gu et al, 1993;Harper et al, 1993;Xiong et al, 1993a), a gene induced by the tumor suppressor p53 (El-Deiry et al, 1993) and a gene whose RNA expression is increased in senescent cells (Noda et al, 1994). In addition to being induced by p53, p21 is also induced by p53-independent pathways (Guo et al, 1995;Halevy et al, 1995;Jiang et al, 1994;Macleod et al, 1995;Michieli et al, 1994;Missero et al, 1995;Parker et al, 1995;Sheikh et al, 1994;Steinman et al, 1994;Zhang et al, 1995). In contrast to the p16 INK4A family, p21 can bind and inhibit a wider spectrum of CDKs .…”

Section: Introductionmentioning

confidence: 99%

Expression of a novel form of p21Cip1/Waf1 in UV-irradiated and transformed cells

Poon

Hunter

1998

Oncogene

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The tumor suppressor p53 and its target the CDK inhibitor p21 (Cip1/Waf1) are key components of the cellular response to DNA damage. Insight into how p21 is regulated in normal cells, and how it may be deregulated in tumor cells is important for the understanding of tumorigenesis. p21 was induced in normal human diploid ®broblasts after UV irradiationinduced DNA damage, but, at a high dose of UV irradiation, a faster mobility form of p21 on SDS ± PAGE (designated p21D) was expressed. Surprisingly, in a variety of growing transformed cell lines, the level of p21 was low but p21D was prominent. We found that p21D appeared to be derived through a loss of around 10 amino acids from the C-terminus of p21, which theoretically would remove the PCNA binding domain, a second cyclin binding domain and the nuclear localization signal sequence. Several characteristics distinguish p21 from p21D. Both the full length p21 and p21D could be stabilized by a proteasome inhibitor, but only the full length p21 was associated with Cdk2 and PCNA. Consistent with this, gel ®ltration chromatography revealed that all the full length p21 in the cell was complexed to other proteins, whereas a signi®cant portion of p21D was in monomeric form. Moreover, p21 was mainly localized to the nucleus, but p21D was mainly localized to the cytoplasm. We propose that the decrease in p21 and increase in p21D could contribute to the deregulation of the cell cycle, and could be a mechanism involved in cellular transformation.

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“…Although the cyclin-dependent kinase inhibitor p21WAFl/Cipl has been proposed as the mediator of p53-induced cell cycle arrest after DNA damage, it has been shown that several stimuli now appear to induce its expression, independent of p53 function. The up-regulation of p21 has also been implicated during normal tissue development and differentiation (Macleod et al, 1995;Missero et al, 1995;Parker et al, 1995).…”

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confidence: 99%

Characterization of keratin and cell cycle protein expression in cell lines from squamous intraepithelial lesions progressing towards a malignant phenotype

Hietanen

Syrjänen²,

Syrjänen³

1998

Br J Cancer

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Summary Two cell lines derived from vaginal intraepithelial neoplasias (VAINs) expressing human papillomavirus (HPV) 33 (VAIN I, UT-DEC-1) and 16 (VAIN II, UT-DEC-2) E6-E7 mRNA were studied in organotypic culture for their keratins and cell cycle regulatory proteins in relation to replicative aging. Early-passage UT-DEC-1 and UT-DEC-2 cells reproduced epithelial patterns consistent with VAIN. Cells from later passages resembled full-thickness intraepithelial neoplasia (UT-DEC-1) and microinvasive cancer (UT-DEC-2). The morphological changes were compatible with these cell lines' ability for anchorage-independent growth at later passages. Simple epithelial keratins were aberrantly expressed in both cell lines. K18 (absent in normal vaginal keratinocytes) and K17 expression increased in UT-DEC-1 and UT-DEC-2 cells at late passages. No marked differences in expression of p53 (wild type in both cell lines), mdm-2 or PCNA were detected in parallel with progression. The expression of p21WAF1/CIp1 localized mostly to the upper half of the epithelium at early passage and was more intense in the HPV 16-positive UT-DEC-2 cell line expressing K10. In Northern blot analyses, the transcription pattern of the HPV 33 E6-E7 of the UT-DEC-1 cell line changed during later passages, whereas that of the HPV 16 E6-E7 of the UT-DEC-2 cell line remained unaltered. The present characterization of the phenotype of these cell lines derived from natural squamous intraepithelial lesions shows an association between simple epithelial-type keratin expression and progressive changes in growth and morphology, but fails to demonstrate consistent changes in the expression of cell cycle regulatory proteins studied in parallel with progression.

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p53-Independent Expression of p21 ^Cip1 in Muscle and Other Terminally Differentiating Cells

Cited by 982 publications

References 48 publications

Rhabdomyosarcoma – working out the pathways

Rhabdomyosarcoma – working out the pathways

Expression of a novel form of p21Cip1/Waf1 in UV-irradiated and transformed cells

Characterization of keratin and cell cycle protein expression in cell lines from squamous intraepithelial lesions progressing towards a malignant phenotype

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p53-Independent Expression of p21 Cip1 in Muscle and Other Terminally Differentiating Cells

Cited by 982 publications

References 48 publications

Rhabdomyosarcoma – working out the pathways

Rhabdomyosarcoma – working out the pathways

Expression of a novel form of p21Cip1/Waf1 in UV-irradiated and transformed cells

Characterization of keratin and cell cycle protein expression in cell lines from squamous intraepithelial lesions progressing towards a malignant phenotype

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p53-Independent Expression of p21 ^Cip1 in Muscle and Other Terminally Differentiating Cells