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At least 181 records · Page 10Linked to original sources
PubMed1993

Reconstitution of the RB gene suppresses the growth of small-cell lung carcinoma cells carrying multiple genetic alterations.

Multiple genetic alterations, including inactivation of the RB gene, occur commonly in small-cell lung carcinoma (SCLC). To assess a functional role of RB inactivation in the development of SCLC, an RB expression plasmid was introduced by stable transfection into SCLC cell lines, Lu-135 and N417, in which the RB gene was inactivated. Lu-135 and N417 cells transfected with the wild-type RB gene formed G418-resistant colonies twofold less efficiently than those with a mutated RB gene or with the control vector. Intact exogenous wild-type RB genes were detected only in approximately 20% of G418-resistant clones; three of 14 in Lu-135 and three of 16 in N417, respectively. Transcripts from the transfected RB gene were also detected in two of these three clones from Lu-135 and two of three from N417 but the amount of RB mRNA and protein was less than one fifth of that in normal fibroblast cells WI-38. Furthermore, clones with exogenous wild-type RB expression showed either reduced growth rates in culture or suppressed tumorigenicity in nude mice. These findings suggest that functional correction of the RB gene is sufficient to suppress the growth of SCLC cells, even though several other genetic alterations in the cells remain uncorrected.

Animals↗
PubMed1996

Role of p53 and RB on in vitro growth of normal umbilical cord blood cells.

Human umbilical cord blood (UCB) is rich in hematopoietic stem cells and progenitors and recently has been used in the clinic as an alternative source for graft and marrow repopulation. We tried to determine in vitro the roles of wild-type (wt) p53 and wt RB tumor/growth suppressor genes in the regulation of proliferation and maturation of hematopoietic UCB cells. CD34+ cells, isolated from mononuclear cells of UCB, were cultured in semisolid medium under conditions that favor growth of hematopoietic cells. We studied the level of expression of p53 and RB mRNAs and proteins during cell culture by Northern blot and cytofluorometry analysis, respectively. Sense (S), antisense (AS), or scrambled (missense [MS]) p53 and RB oligodeoxynucleotides (ODNs) were used to study the behavior of these cells in the absence of expression of p53 and/or RB. Adequate doses of p53 or RB ODNs inducing maximal inhibitory effect were used to study the behavior of these cells in the absence of expression of p53 and/or RB. Adequate doses of p53 or RB ODNs inducing maximal inhibitory effect with minimal cellular toxicity were determined. Exposure of CD34+ cells to p53 or AS, RB AS, or both p53 and RB AS but not other ODNs (sense or missense) resulted in a significantly increased number of colony-forming units-granulocyte/macrophage (CFU-GM) induced by interleukin-3 (IL-3) and/or granulocyte-macrophage colony-stimulating factor (GM-CSF). The number of erythroid colonies (CFU-E) and burst-forming units (BFU-E) derived from CD34+ cells in the presence of erythropoietin (Epo) was not significantly increased, whereas the number of such colonies was markedly increased in the presence of IL-3 + EPO upon p53 AS and/or RB AS treatment with hypothesis that wt p53 and RB are proliferation suppressor genes that interfere with normal maturation of hematopoietic cells.

Antigens, CD34↗
PubMedDate not supplied

Promoter-independent loss of mRNA and protein of the Rb gene in a human hepatocellular carcinoma.

BACKGROUND: Inactivation of the retinoblastoma (Rb) gene is considered to play a fundamental role in the genesis and progression of several human cancers. In retinoblastoma, the inactivation of Rb promoter by mutations or hypermethylation has been reported. Although genetic changes of Rb gene have been described in hepatocellular carcinoma (HCC), an epigenetic change such as hypermethylation of the Rb promoter as reported in retinoblastoma has not been described. MATERIALS AND METHODS: We examined the hypermethylation in the promoter region of Rb gene by restriction fragment length polymorphism in 19 HCCs, as well as the expression of Rb mRNA and protein by RT-PCR and by immunoblotting, respectively. RESULTS: We found no evidence of hypermethylation in the promoter region of the Rb gene in all HCCs analyzed. However, the expression of Rb mRNA and protein was lost in one HCC, and no mutation was detected in the Rb promoter region of this patient. The inactivation of Rb promoter by hypermethylation or by inhibition of binding of transcription factors due to point mutations did not contribute to the loss of mRNA and protein in the patient. CONCLUSIONS: Hypermethylation in the Rb promoter region appeared to have little causal effect on HCC.

Aged↗
PubMed1993

C-FMS dependent HL-60 cell differentiation and regulation of RB gene expression.

The dependence of induced myelomonocytic cell differentiation, and regulation of the RB tumor suppressor gene during this process, on the c-fms gene product, the CSF-1 lymphokine receptor, was determined in HL-60 promyelocytic leukemia cells. Adding a monoclonal antibody with specificity for the c-fms gene product to cells treated with various inducers of myelomonocytic or macrophage differentiation, including retinoic acid and 1,25-dihydroxy vitamin D3, inhibited the rate of differentiation. During the period of inducer treatment usually preceding onset of differentiation, longer periods of antibody exposure caused greater inhibition of differentiation. In a stable HL-60 transfectant overexpressing the CSF-1 receptor at the cell surface due to a constitutively driven c-fms trans gene, the rate of differentiation was enhanced compared to the wild type cell, consistent with a positive regulatory role for the CSF-1 receptor. The anti-fms antibody caused much less inhibition of differentiation in the transfectants than in wild type cells, consistent with a larger number of receptors causing reduced sensitivity. During the induced metabolic cascade leading to differentiation, the typical early down regulation of RB gene expression was inhibited by the antibody. The antibody itself caused an increase in RB expression per cell, which offset the decrease normally caused by differentiation inducers (1,25-dihydroxy vitamin D3 and retinoic acid). The changes in RB expression preceded changes in the RB protein to the hypophosphorylated state. Most of the RB protein in proliferating cells was phosphorylated and no significant accumulation of hypophosphorylated RB protein occurred until after onset of G0 arrest. Thus the metabolic cascade leading to myelomonocytic differentiation of HL-60 cells appears to be driven by a function of the c-fms protein. Inhibiting that process by attacking this receptor impedes differentiation and also compromises the early down regulation of RB tumor suppressor gene expression which normally precedes differentiation. These findings provide additional support for a potential role for down regulating RB expression in promoting cell differentiation, and suggest the possibility that RB may be either a target or intermediate mediator of CSF-1 actions.

Antibodies, Monoclonal↗
PubMed1998

Cellular resistance to adriamycin conferred by enhanced Rb expression is associated with increased MDR1 expression.

In order to investigate if the enhanced expression of Rb confers increased cellular resistance to adriamycin, we made Rb stable transfectants from colon carcinoma cells, SW620. Rb stable transfectants exhibited 5- to 10-fold more resistance to adriamycin than the control cells. To study the correlation between enhanced Rb expression and MDR1 expression, products of the Rb gene and the MDR1 gene in Rb stable transfectants were measured by Western blot analysis. These Rb transfectants showed increased MDR1 expression. Transient transfection of the MDR1 promoter-CAT reporter gene and the Rb gene demonstrated that Rb up-regulated MDR1 promoter activity in SW620 cells. Rb may, at least partly, contribute to a role in protecting cells from carcinogen exposure by up-regulating the MDR1 gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

E2F1 and p53 are dispensable, whereas p21(Waf1/Cip1) cooperates with Rb to restrict endoreduplication and apoptosis during skeletal myogenesis.

We describe temporal and genetic analyses of partially rescued Rb mutant fetuses, mgRb:Rb-/-, that survive to birth and reveal specific defects in skeletal muscle differentiation. We show that in the absence of Rb, these fetuses exhibit increased apoptosis, bona fide endoreduplication, and incomplete differentiation throughout terminal myogenesis. These defects were further augmented in composite mutant fetuses, mgRb:Rb-/-:p21-/-, lacking both Rb and the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Although E2F1 and p53 mediate ectopic DNA synthesis and cell death in several tissues in Rb mutant embryos, both endoreduplication and apoptosis persisted in mgRb:Rb-/-:E2F1-/- and mgRb:Rb-/-:p53-/- compound mutant muscles. Thus, combined inactivation of Rb and p21(Waf1/Cip1) augments endoreduplication and apoptosis, whereas E2F1 and p53 are dispensable during aberrant myogenesis in Rb-deficient fetuses.

Animals↗
PubMed1994

Late dephosphorylation of the RB protein in G2 during the process of induced cell differentiation.

The cell cycle phase-specific phosphorylation status of the RB protein (retinoblastoma tumor suppressor gene product) during an elicited cellular program of G0 arrest and cell differentiation was characterized. The RB protein phosphorylation state is presumed to be an important determinant of cell proliferation or arrest. The cell cycle phase specificity of RB protein phosphorylation and dephosphorylation during HL-60 human leukemia cell proliferation and differentiation was determined using DNA-based fluorescence-activated cell sorting and Western analysis. The RB protein in proliferating G1 cells was phosphorylated, but at a relatively low level. The extent of phosphorylation increased in S phase cells and was maximum in G2 + M cells. After the cells were treated with retinoic acid or 1,25-dihydroxy vitamin D3, they began to accumulate in G1/0 and phenotypically convert. Significant unphosphorylated RB protein did not appear until after the first cells had arrested and differentiated. Dephosphorylation of the RB protein was first apparent at the beginning of G2 in the remaining cycling cells after onset of arrest and differentiation had already occurred. By the time the remaining cycling cells had divided and arrested, resulting in G0 cells, a majority of RB protein was dephosphorylated, but some remained phosphorylated. The data indicate that dephosphorylation of RB does not determine residence in G1/0. Rather dephosphorylation appears as one relatively late-occurring component of the metabolic cascade culminating in G0-arrested, phenotypically differentiated cells. Dephosphorylated RB appears as a feature of differentiated cells. The data are consistent with a role for hypophosphorylated RB not so much in deriving, but in possibly sustaining the differentiated state.

Blotting, Western↗
PubMed1998

Expression of p16INK4 and retinoblastoma protein Rb in vulvar lesions of Chinese women.

The protein products of the two tumor suppressor genes located on 9p and 13p, p16INK4 and Rb, respectively, play an important role in regulation of the cell cycle and are implicated in tumorigenesis. We examined 49 cases of benign vulvar lesions, vulvar intraepithelial neoplasia (VIN), and squamous cell carcinoma with immunohistochemical staining to determine expression of p16INK4 and Rb. All and 86% of benign lesions expressed Rb and p16INK4, respectively; 40% each of VIN I and VIN III expressed p16INK4 and Rb, respectively; and 37 and 68% of squamous cell carcinomas expressed p16INK4 and Rb, respectively. The combination of the lack of p16INK4 and/or Rb expression increased from benign lesions (14.3%), through VIN I (60%) and VIN III (60%), to invasive squamous cell carcinoma (72%), thus supporting the postulation that alterations in p16INK4 or Rb could be significant events in progression of disease. The loss of Rb expression also increased from stage I carcinoma (16.7%) through stage II (26.7%) and III (44.4%), to IV (50%), suggesting that Rb may play an important role in tumor progression. A larger study on VIN lesions and genetic coding is suggested to further investigate the role of p16INK4, Rb, and other factors in tumorigenesis and progression of vulvar cancers.

Carcinoma, Squamous Cell↗
PubMed1995

Reduced expression of retinoblastoma (Rb) gene protein is related to cell proliferation and prognosis in transitional-cell bladder cancer.

Archival biopsy specimens from transitional-cell bladder cancers (n = 222) were analysed immunohisto-chemically for expression of retinoblastoma (Rb) gene protein. The intensity of staining for Rb protein and the fraction of positive nuclei were analysed and related to several other prognostic factors and survival. Six per cent of the tumours were totally negative for Rb protein and abnormal (weak) expression was found in 40% of cases. The fraction of positive nuclei and abnormal expression (weak) were highly significantly interrelated (P < 0.0001). A low value for the fraction of Rb-protein-positive nuclei was related to a large fraction in S phase (P = 0.001), high mitotic index (P = 0.016) and overexpression of epidermal growth factor receptor (P = 0.034) and p53 protein (P = 0.019). A normal Rb protein expression pattern was related to low S-phase values (P = 0.0001) whereas over-expression of p53 was related to high S-phase values (P = 0.0077). Morphometrically measured nuclear atypia and the fraction of Rb-protein-positive nuclei were negatively correlated (P < 0.05). In univariate survival analysis altered expression of Rb protein (P = 0.07) and low frequency (< or = 50%) of Rb-protein-positive nuclei (P = 0.0128) predicted a poor outcome. In a multivariate analysis, reduced expression of Rb protein had no independent prognostic value over T category, papillary status and the size of the S-phase fraction. The results show that tumor-suppressor genes Rb and p53 participate in the growth regulation of human bladder cancer cells in vivo and accordingly modify the prognosis.

Adult↗
PubMed1999

Expression of p53, p21/waf, bcl-2, bax, Rb and Ki67 proteins in colorectal adenocarcinomas.

This study investigated the combined immunoexpression of p53, p21, bcl-2, bax, Rb and Ki67 proteins in colorectal adenocarcinomas and correlated expression patterns with tumour stage and grade. Paraffin sections from 98 cases of colorectal adenocarcinomas were stained by immunohistochemistry for p53, p21, bcl-2, bax, Rb and MIB-1 (Ki67) proteins. In addition, 12 cases of colorectal adenomas and normal colorectal mucosa were studied in parallel. P53, p21, bcl-2, bax, Rb and Ki67 proteins were detected in at least 5% of tumour cells in 63/98, 72/98, 52/98, 96/98 and 98/98 adenocarcinomas, respectively. Comparative study of the normal-adenoma-carcinoma tissues revealed abrogation of the normal immunotopography in adenomas and adenocarcinomas, and considerable modifications, increase or reduction, of the expression of p53, p21, bcl-2, bax, Rb and Ki67 proteins in adenocarcinomas when compared with normal mucosa and adenomas. Statistically significant correlations were found between low bax expression and Dukes C stage of carcinomas, Ki67 expression and carcinoma grade, and Ki67 and Rb expression. P53, p21, bcl-2 and Rb immunoexpression did not correlate with tumour stage or grade. Our findings show that low bax immunoexpression is frequently related to colorectal adenocarcinomas with lymph node metastases suggesting that low levels of bax expression play a role in late stage colorectal cancer. The correlation between Ki67 and Rb expression, in view of previous data that the hyperphosphorylated inactive Rb protein is frequently increased in colorectal adenocarcinomas, suggests that Rb protein is somewhat ineffective in inhibiting the cell-cycle progression in these malignancies. Furthermore, our findings provide immunohistochemical evidence that the abrogation of the normal immunotopography and the modifications of the expression of p53, p21, bcl-2, bax, Rb and Ki67 proteins reflect important events in colorectal oncogenesis.

Adenocarcinoma↗
PubMed2006

Dephosphorylation of Rb (Thr-821) in response to cell stress.

The retinoblastoma tumor suppressor Rb is regulated by reversible phosphorylation that is dependent upon cyclin-dependent kinase (CDK) and protein phosphatase type 1 (PP1) activity in replicating cells. Hyperphosphorylated Rb allows cells to proliferate, whereas the hypophosphorylated isoform of Rb inhibits proliferation. Of the many phosphorylation sites of Rb, there is functional information available for a very few. In this report, we show that threonine-821 (Thr-821) of Rb is dephosphorylated earlier than other phosphorylation sites when cells are grown under hypoxic conditions which leads to Rb activation and G(1) arrest. This finding is interesting because Thr-821 of Rb remains phosphorylated throughout the cell division cycle in replicating cells. We hypothesized that the phosphorylation state of Thr-821 of Rb may depend on cellular stress. We report in this study that, when nontransformed CV1 epithelial cells and Hs578T breast cancer cells are treated with the chemotherapeutic agent cytosine arabinoside (Ara-C), Thr-821 of Rb is rapidly dephosphorylated concomitant with dissociation of the PP1 regulatory subunit PNUTS (phosphatase nuclear targeting subunit) from PP1 enzyme. These data are consistent with the concept that differential regulation of Rb-directed phosphatase activity exists when cells are progressing through the cell cycle compared to that observed when cells are under stress.

Antimetabolites, Antineoplastic↗
PubMed1992

Abrogation by c-myc of G1 phase arrest induced by RB protein but not by p53.

Inactivating mutations of the retinoblastoma gene (RB) are found in a wide variety of tumour cells. Replacement of wild-type RB can suppress the tumorigenicity of some of these cells, suggesting that the RB protein (Rb) may negatively regulate cell growth. As activation of c-myc expression promotes cell proliferation and blocks differentiation, it may positively regulate cell growth. The c-myc protein is localized in the nucleus and can physically associate with RB protein in vitro, hence c-myc may functionally antagonize RB function. Microinjection of Rb in G1 phase reversibly arrests cell-cycle progression. Here we co-inject RB protein with c-myc, EJ-ras, c-fos or c-jun protein. Co-injection of c-myc, but not EJ-ras, c-fos or c-jun, inhibits the ability of Rb to arrest the cell cycle. The c-myc does not inhibit the activity of another tumour supressor, p53 (ref. 12). Thus, c-myc and RB specifically antagonize one another in the cell.

Animals↗
PubMed1997

Rb interacts with TAF(II)250/TFIID through multiple domains.

The retinoblastoma tumor suppressor gene product (Rb) binds directly to the largest TFIID subunit, TATA-binding protein associated factor TAF(II)250, first identified as the cell cycle regulatory protein CCG1. Here we map the domains in Rb and TAF(II)250 important for their interaction in vitro and in vivo. Both the amino terminus and the large pocket of Rb are able to associate independently with TAF(II)250. The binding domain(s) within the large pocket are distinct from the viral oncoprotein and E2F binding region since certain pocket mutations, which abolish E1A binding, do not abolish TAF(II)250 binding. Consistent with the large pocket of Rb binding to TAF(II)250, the large pocket domains of both p107 and p130 are able to bind to TAF(II)250 in vivo. We also demonstrate that at least two regions of TAF(II)250 are able to bind to the large pocket of Rb independently whereas the amino terminus of Rb binds to a distinct domain in TAF(II)250. We further demonstrate that Rb can bind to TFIID in vitro, presumably in part through an interaction with TAF(II)250. Our results suggest a complex interaction between Rb and TAF(II)250 and imply that TAF(II)250, TFIID, and potentially other basal transcription factors are targets for regulation by Rb and Rb-related proteins.

Binding Sites↗
PubMed2001

RB regulates transcription of the p21/WAF1/CIP1 gene.

We have previously shown that RB plays an important role in the maintenance of the epithelial phenotype. p21 is also involved in several terminal differentiation systems including keratinocytes. We report here that p21 is an RB target gene in epithelial cells, but not in fibroblasts where RB is unable to transactivate p21 transcriptional expression. In epithelial cells, when RB family factors were inactivated by SV40 T antigen (LT), p21 expression was strongly repressed, whereas its expression was not affected when the cells were transformed by a mutated LT leaving RB active but inactivating p53. Moreover, retransformation by RB of LT transformed epithelial cells totally restored p21 expression. By cotransfection experiments and using deletions and point mutations of the p21 promoter, we show that the minimal region required for the RB-mediated transcriptional activation maps to a GC-rich region located between -83 and -74. This region is shown to interact specifically with the transcription factor Sp1 and Sp3. Thus for the first time, we show a positive transcriptional relationship between RB and p21 in epithelial cells. Since p21 keeps RB in a hypophosphorylated state important for its transcriptional activity during differentiation, our results imply an auto-loop of regulation between RB and p21 that may be essential for the maintenance of the differentiation state. We propose that this transcriptional relationship might be necessary of their roles in cell cycle arrest and in several differentiation pathways.

Animals↗
PubMed2003

Apoptotic and mitogenic stimuli inactivate Rb by differential utilization of p38 and cyclin-dependent kinases.

Inactivation of the retinoblastoma (Rb) tumor suppressor protein is essential for the G1/S transition during mammalian cell cycle progression. Although Rb is inactivated by phosphorylation by cyclins D and E and their associated kinases during cell cycle progression, we find that Rb is inactivated upon apoptotic stimulation by Fas through the mediation of p38 kinase, independent of cyclins and cyclin-dependent kinases (cdks). Inactivation by p38 kinase coincided with increased phosphorylation of Rb leading to dissociation of E2F and increased transcriptional activity; such p38-mediated changes in Rb function occurred only during Fas stimulation but not mitogenic progression. p38 kinase targets Rb preferentially and had minimal effects on p107 and had no effect on p130 function. We also find that phosphorylation site mutants of Rb (PSM7LP and PSM9-Rb) that cannot be inactivated by cdks can be targeted by Fas and p38 kinase, suggesting that Rb inactivation by these kinases is biochemically and functionally distinct. It appears that Rb inactivation is achieved by different kinase cascades in response to mitogenic and apoptotic signals.

Apoptosis↗
PubMed2004

Differential regulation of apoptotic genes by Rb in human versus mouse cells.

The retinoblastoma protein (Rb) controls cellular proliferation and suppresses tumor formation through its effects upon E2F transcriptional regulation of the cell cycle. Unexpectedly, however, in proliferating human cells, Rb was present at the promoters of eight of eight E2F-regulated apoptotic genes tested, but zero of six E2F-regulated cell cycle genes tested. Binding of apoptotic gene promoters by Rb was constitutive, and inhibition of Rb in human cells by E2Fdb or E1A expression resulted in induction of these apoptotic genes and efficient cell death. E1A induced apoptosis much more efficiently in human fibroblasts than in mouse fibroblasts, suggesting a difference in susceptibility to loss of Rb function between human cells and mouse cells. Abrogation of Rb function in mouse cells did not induce expression of these apoptotic genes. Underlying this species difference in susceptibility to apoptosis following loss of Rb function was the absence of Rb on apoptotic gene promoters in mouse cells. Rb protein levels were 20-35-fold higher in primary human cells than in primary mouse cells. The constitutive repression of a multitude of apoptotic genes by Rb in human cells but not in mouse cells may provide a partial explanation for the well-known difference between human and mouse cells in transformation and tumorigenic potential.

Animals↗
PubMed2005

Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis.

Here, we describe the surprising residual capability of the Rb pathway to negatively regulate proliferation and tumorigenesis in a SV40 large T antigen (Tag)-driven mouse model of pancreatic islet carcinogenesis. Heterogeneous Tag expression during all progression stages suggested that a threshold level of the T antigen oncoprotein might be deterministic for beta-cell hyperproliferation and led us to hypothesize that Tag might not be fully inhibiting the tumor suppressor activity of Rb. Moreover, genomic profiling of these tumors by array CGH pointed to regions of loss on chromosomes 6 and 14, where the Rb pathway inhibitor p27 and Rb itself, respectively, reside. Indeed, genetic ablation of the p27(Kip1) or Rb genes accentuated Tag-induced tumorigenesis, with loss of Rb in particular broadly enhancing multiple parameters of tumorigenesis including the frequency and growth rates of premalignant lesions, of nascent solid tumors, and of invasive carcinomas. The data indicate that attenuation rather than complete inactivation of Rb tumor suppressor gene function, in the context of p53 inhibition, is sufficient to initiate tumorigenesis in this model of islet cell cancer, with the demonstrable possibility that subsequent losses of Rb or its regulators can enhance malignant progression. The results may be relevant to human papillomavirus (HPV)-induced cervical neoplasias where E7 oncogene expression levels or activity (in the case of intermediate/low-risk HPV subtypes) incompletely inhibits Rb tumor suppressor functions, as well as to other neoplasias where initiating oncogenic or tumor suppressor events reduce but do not abrogate Rb function.

Animals↗
PubMed2006

Phosphorylation site mutated RB exerts contrasting effects on apoptotic response to different stimuli.

The retinoblastoma tumor-suppressor protein (RB) is an important regulator of cell cycle and apoptosis. RB is phosphorylated by cyclin-dependent protein kinase during cell cycle progression. A phosphorylation site mutated (PSM)-RB has previously been shown to cause G1 arrest and to interfere with S phase progression. In this study, we examined the effect of inducible PSM-RB expression on the apoptotic response to three different death stimuli: doxorubicin (DOXO), staurosporine (STS) and tumor necrosis factor (TNF) in Rat-16 cells. Induced expression of PSM-RB attenuated caspase activation by DOXO as a result of cell cycle arrest. STS has been shown to cause RB-dependent G1 arrest or apoptosis; however, expression of PSM-RB did not prevent caspase activation by STS. Surprisingly, induced expression of PSM-RB stimulated the apoptotic response to TNF in Rat-16 cells, which mostly undergo necrosis in the absence of PSM-RB. These results show that PSM-RB exerts disparate effects on apoptotic response to different stimuli, and that cell cycle arrest does not always associate with resistance to apoptosis.

Animals↗