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PubMed2004

Seroprevalence of Toxoplasma gondii in American free-ranging or captive pumas (Felis concolor) and bobcats (Lynx rufus).

Toxoplasma gondii is a major zoonotic agent infecting a wide range of mammals, including wild felids. Like domestic cats, wild felids are involved in the complete infective cycle of T. gondii, as they can host in their gastrointestinal tract sexually mature parasites and shed infective oocysts in their feces. In order to evaluate the importance of this wildlife reservoir, 438 serum samples collected between 1984 and 1999 from 438 pumas (Felis concolor) and from 58 bobcats (Lynx rufus) from North America, Central America and South America were screened for antibodies to T. gondii. The overall prevalence of T. gondii antibodies was 22.4% in pumas and 51.7% in bobcats, with regional variations. Adults were more likely to be seropositive than juveniles and kittens (prevalence ratio (PR) = 2.61; confidence interval (CI) = 1.15, 4.04). In the US, pumas from the southwestern states (Arizona, California and New Mexico) were more likely to be seropositive for T. gondii ( PR = 2.61; 95% CI = 1.32-5.18 ) than pumas from the northwestern and mountain states (Colorado, Idaho, Oregon, Utah and Wyoming). Male pumas from the US were more likely to be seropositive than females (PR = 2.08; 95% CI = 1.11-3.92), whereas female pumas from Mexico, Central America and South America were more likely to be seropositive than female pumas from Canada and the US (PR = 2.49; 95% CI = 1.09-5.69). Captive pumas were also more likely to be seropositive (21.7%, 29/92) for T. gondii than free-ranging animals (19.9%, 69/346) (PR = 1.85; 95% CI = 1.06, 3.17).

Animals↗

PubMed2005

PUMA expression is significantly reduced in human cutaneous melanomas.

Cutaneous malignant melanoma is an aggressive form of skin cancer, characterized by strong chemoresistance and poor patient prognosis. The molecular mechanisms underlying its resistance to chemotherapy remain unclear but are speculated to involve the dysregulation of apoptotic pathways. In this study, we sought to determine whether PUMA (p53 upregulated modulator of apoptosis) contributes to human melanoma formation, tumor progression, and survival. We used tissue microarray and immunohistochemistry to examine PUMA expression in 107 primary melanomas, 51 metastatic melanomas, and 64 dysplastic nevi. Here we report that PUMA expression is significantly weaker in primary melanomas compared to dysplastic nevi (P<0.0001), and is further reduced in metastatic melanomas compared to primary tumors (P=0.001). We show that weak PUMA expression in melanoma correlates with poorer overall and disease-specific 5-year survival (P<0.005 and P<0.001, respectively) of melanoma patients and that PUMA expression in tumor tissue is an independent predictor of both overall and disease-specific 5-year survival (P=0.05). Additionally, we show that exogenous PUMA expression in human melanoma cell lines (both wild type and mutant p53) results in significant apoptotic cell death. Our results suggest that PUMA expression may be an important prognostic marker for human melanoma and that adenoviral delivery of PUMA sensitizes melanoma cells to apoptosis.

Adult↗

PubMed2006

Regulation of PUMA-alpha by p53 in cisplatin-induced renal cell apoptosis.

Nephrotoxicity is a major side effect of cisplatin, a widely used cancer therapy drug. Depending on its concentration, cisplatin induces necrosis or apoptosis of tubular cells in the kidneys, whereas the underlying injury mechanism is unclear. Our recent work has suggested a critical role for p53 in cisplatin-induced tubular cell apoptosis; nevertheless, the apoptotic events triggered by p53 remain elusive. The current study has examined Bcl-2 family proteins, critical regulators of apoptosis that may be subjected to p53 regulation. Following cisplatin treatment, the expression of Bcl-xL, an antiapoptotic molecule, was suppressed, while the expression of Bak, a proapoptotic molecule, increased slightly. Of interest, PUMA-alpha, a newly identified p53-responsive proapoptotic Bcl-2 family protein, was drastically induced by cisplatin. PUMA-alpha induction preceded or paralleled the development of apoptosis. Induced PUMA-alpha was localized in mitochondria and appeared to antagonize Bcl-xL via molecular interaction. PUMA-alpha induction during cisplatin treatment was attenuated by pifithrin-alpha, a pharmacological inhibitor of p53, which was accompanied by the amelioration of Bax activation, cytochrome c release and apoptosis. Moreover, PUMA-alpha induction was suppressed by dominant-negative p53. Importantly, cisplatin-induced apoptosis was ameliorated in PUMA-alpha knockout cells. In vivo, cisplatin induced PUMA-alpha in the kidneys, and the inductive response was abrogated in p53-deficient animals. Together, this study has demonstrated the first compelling evidence for the involvement of PUMA-alpha in p53-mediated renal cell apoptosis during cisplatin nephrotoxicity.

Animals↗

PubMed2005

Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status.

Replacement of the p53 tumor suppressor gene is a rational approach to the management of malignant gliomas because p53 is frequently mutated or inactivated in these cancers. Major weaknesses of this approach are that malignant gliomas are mixtures of cells with wild-type and mutant p53, and that tumor cells exhibiting wildtype p53 are resistant to p53 gene transfer. An effective alternative is needed to overcome these difficulties. p53-upregulated modulator of apoptosis (PUMA) was identified as a p53-inducible proapoptotic molecule. Our purpose was to elucidate a role for PUMA in p53 gene therapy and to investigate whether PUMA is an efficient substitute for p53 in cancer therapy. We demonstrated that PUMA was upregulated in mutant p53 malignant glioma cells (U373-MG and T98G) undergoing apoptosis but was not upregulated in apoptosis-resistant wild-type p53 malignant glioma cells (U87-MG and D54) after adenoviral transfer of p53. Overexpression of PUMA resulted in massive apoptosis associated with mitochondrial damage and caspase-3 activation in all tumor cells tested. Use of the human telomerase reverse transcriptase (hTERT) promoter system induced apoptosis only in malignant glioma cells with telomerase activity, while sparing normal cells lacking telomerase. The ability of PUMA to induce apoptosis was greater than that of caspase-6 or caspase-8 transfer, using the same system. Moreover, exogenous expression of PUMA under the hTERT promoter system significantly suppressed the growth of subcutaneous U87-MG tumors in nude mice and did not induce apoptosis in surrounding nontumor tissues. These results indicate that PUMA, which is regulated under a tumor-specific expression system such as the hTERT promoter, may be better than p53 as a therapeutic tool for malignant gliomas.

Adenoviridae↗

PubMed1988

A comparative analysis of ejaculate and hormonal characteristics of the captive male cheetah, tiger, leopard, and puma.

Male cheetahs, tigers, leopards, and pumas maintained under the same conditions were anesthetized and 1) serially bled before, during, and after electroejaculation (EE); 2) serially bled only (AO); or 3) serially bled before and after receiving adrenocorticotropin hormone (ACTH). Ejaculates from leopards contained higher (p less than 0.05) sperm concentrations than cheetahs and pumas but lower (p less than 0.05) sperm motility ratings than all other species. Tigers produced a larger seminal volume and the greatest number of motile sperm/ejaculate (p less than 0.05). The percentage of morphologically abnormal spermatozoa was greater (p less than 0.05) in cheetahs (64.6%), leopards (79.5%), and pumas (73.5%) than in tigers (37.5%). The most prevalent spermatozoal deformities included a tightly coiled or bent flagellum, a deranged midpiece, or a residual cytoplasmic droplet. Mean baseline serum cortisol concentrations in leopards were 2- and 4-fold greater (p less than 0.05) than in tigers and cheetahs, respectively. Basal cortisol concentrations in pumas were similar to those of tigers, but irrespective of treatment increased 2-fold (p less than 0.01) during the bleeding period. An acute rise and fall in cortisol attributable to EE was observed only in cheetahs. In tigers and leopards, mean peak cortisol concentrations after ACTH were similar to maximal values observed after EE. However, peak cortisol levels in cheetahs and pumas after ACTH were greater (p less than 0.01) than the concentrations measured after EE, indicating that these manipulatory procedures were not eliciting a maximal adrenal response. In the EE groups, luteinizing hormone (LH) and testosterone levels in cheetahs were lower (p less than 0.05) than in other species, whereas levels of both hormones were comparable (p greater than 0.05) in tigers, leopards, and pumas. Elevated cortisol levels in cheetahs and pumas had no discernible effect on LH/testosterone patterns; however, the results were equivocal in tigers, and, among leopards, testosterone concentrations consistently declined over time. In this study, using a standardized approach, we identify different ejaculate and endocrine characteristics of captive cheetahs, tigers, leopards, and pumas. The data extend earlier observations and demonstrate that some, but not all, Felidae species ejaculate high numbers of pleiomorphic spermatozoa. However, inter-species differences in sperm integrity do not appear related to inter-species variations in cortisol, LH, or testosterone. The observation of continuously declining testosterone concentrations only in leopards after AO, EE, or ACTH treatment suggests that rising and/or elevated cortiso

Acinonyx↗

PubMed2006

PUMA-mediated apoptosis in fibroblast-like synoviocytes does not require p53.

PUMA (p53-upregulated modulator of apoptosis) is a pro-apoptotic gene that can induce rapid cell death through a p53-dependent mechanism. However, the efficacy of PUMA gene therapy to induce synovial apoptosis in rheumatoid arthritis might have limited efficacy if p53 expression or function is deficient. To evaluate this issue, studies were performed to determine whether p53 is required for PUMA-mediated apoptosis in fibroblast-like synoviocytes (FLS). p53 protein was depleted or inhibited in human FLS by using p53 siRNA or a dominant-negative p53 protein. Wild-type and p53-/- murine FLS were also examined to evaluate whether p53 is required. p53-deficient or control FLS were transfected with PUMA cDNA or empty vector. p53 and p21 expression were then determined by Western blot analysis. Apoptosis was assayed by ELISA to measure histone release and caspase-3 activation, or by trypan blue dye exclusion to measure cell viability. Initial studies showed that p53 siRNA decreased p53 expression by more than 98% in human FLS. Loss of p53 increased the growth rate of cells and suppressed p21 expression. However, PUMA still induced apoptosis in control and p53-deficient FLS after PUMA cDNA transfection. Similar results were observed in p53-/- murine FLS or in human FLS transfected with a dominant-negative mutant p53 gene. These data suggest that PUMA-induced apoptosis in FLS does not require p53. Therefore, approaches to gene therapy that involve increasing PUMA expression could be an effective inducer of synoviocyte cell death in rheumatoid arthritis regardless of the p53 status in the synovium.

Animals↗

PubMed2006

Administration of PUMA adenovirus increases the sensitivity of esophageal cancer cells to anticancer drugs.

Esophageal cancer is one of the most lethal human tumors, characterized by relative chemoresistance and poor prognosis. Researchers have been seeking for multimodality to improve its outcome of therapy. PUMA (p53 upregulated modulator of apoptosis) is a potent proapoptotic molecule that is rapidly induced in cells following DNA damage and is required for p53-induced apoptosis. We evaluated the therapeutic potential of PUMA adenovirus against esophageal cancer cell lines (KYSE-150, KYSE-410, KYSE-510 and YES-2). Infection with Ad-PUMA (PUMA Adenovirus) resulted in the more powerful cytotoxicity in these cell lines compared with Ad-p53. Furthermore, we assessed the efficacy of a combined treatment with Ad-PUMA and anticancer drug (cisplatin, paclitaxel, 5-fluorouracil, respectively) for these cells and found PUMA significantly increased the chemosensitivity of esophageal cancer cells, which may result from more abundant apoptosis induction. Interestingly, Ad-PUMA was found to be more efficient than Ad-p53 in inhibiting cell growth and enhancing the chemosensitivity of esophageal cancer cell lines irrespective of the p53 status. These results suggest that Ad-PUMA is a potent cytotoxic agent and could be a promising alternative in the cancer gene therapy in combination with chemotherapeutic agents.

Antineoplastic Agents↗

PubMed2001

PUMA, a novel proapoptotic gene, is induced by p53.

The p53 tumor-suppressor protein functions as a transcriptional activator, and several p53-inducible genes that play a role in the induction of apoptosis in response to p53 have been described. We have identified a novel gene named PUMA (p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain-containing proteins (PUMA-alpha and PUMA-beta) that are induced in cells following p53 activation. PUMA-alpha and PUMA-beta show similar activities; they bind to Bcl-2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of PUMA expression reduced the apoptotic response to p53, and PUMA is likely to play a role in mediating p53-induced cell death through the cytochrome c/Apaf-1-dependent pathway.

Alternative Splicing↗

PubMed2005

PUMA overexpression induces reactive oxygen species generation and proteasome-mediated stathmin degradation in colorectal cancer cells.

Increased amounts of reactive oxygen species (ROS) induce apoptosis in mammalian cells. PUMA (P53 up-regulated modulator of apoptosis), a mitochondrial proapoptotic BH3-only protein, induces rapid apoptosis through a Bax- and mitochondria-dependent pathway. However, the molecular basis of PUMA-induced apoptosis is largely not understood. Using a combination of biophysical and biochemical methods and PUMA-inducible colorectal cells, DLD-1.PUMA, we showed that (a) PUMA-induced apoptosis is dose and time dependent; (b) PUMA-induced apoptosis is directly associated with ROS generation; (c) diphenyleneiodonium chloride, a ROS blocker, or BAX-inhibiting peptide, a suppressor of BAX translocation, decreased ROS generation and apoptosis in DLD-1.PUMA cells; (d) overexpression of PUMA induced up-regulation (>1.34-fold) of peroxiredoxin 1 and down-regulation (by 25%) of stathmin through proteasome-mediated degradation; and (e) hydrogen peroxide down-regulated stathmin and disrupted the cellular microtubule network. Our findings indicate that PUMA induces apoptosis, in part, through the BAX-dependent generation of superoxide and hydrogen peroxide. ROS overproduction and oxidative stress induce proteome-wise alterations, such as stathmin degradation and disorganization of the cell microtubule network, in apoptotic cells.

Apoptosis↗

PubMed2004

mRNA and protein expression of PUMA in sporadic colorectal cancer.

PUMA is a BH3-only member of the Bcl-2 family, up-regulated by p53 as a response to DNA damage. We have investigated the mRNA expression of PUMA with real-time PCR in 94 colorectal adenocarcinomas and the corresponding normal mucosa. Among them PUMA protein expression was investigated with immunohistochemistry in 23 tumours and 17 corresponding normal mucosa samples. The mRNA expression of PUMA decreased in 4% and increased in 4% of the tumours compared with the normal mucosa. The protein expression of PUMA decreased in 6% and increased in 29% of the tumours compared with the normal mucosa. Decreased PUMA expression in the tumour compared with the corresponding mucosa was correlated with the distal colon and rectum (P=0.02). We did not find any other relationship to clinical or pathological features. We suggest that the changes in PUMA expression may be of minor importance in the development of colorectal cancer.

Adenocarcinoma↗

PubMed2004

[Sensitivity of Chlorella vulgaris to metribuzin, puma and alachlor].

The relative sensitivities of Chlorella vulgaris to three commonly used herbicides metribuzin, puma and alachlor were determined by toxicity tests of 96-h static exposures. The results showed that the toxicities of metribuzin and alachlor to C. vulgaris increased with exposure time, and the density of C. vulgaris decreased with increasing concentrations of these two herbicides in the test media. The maximum specific growth rate of C. vulgaris exposed to metribuzin (0.24 mgL x L(-1)) and alachlor (12.8 mg x L(-1)) was 12.38% and 31.58% of the control, respectively. At low concentration, puma stimulated C. vulgaris growth, but at high concentration, it inhibited the growth significantly. The maximum specific growth rate of C. vulgaris under 0.08 mg x L(-1) puma was 111.44% of the control, and the toxicity of puma declined with increasing exposure duration. The EC50 value of metribuzin, puma and alachlor was 0.021, 0.937, and 5.54 mg x L(-1), respectively. The relative sensitivities of C. vulgaris to the three herbicides decreased in the order of metribuzin, puma and alachlor. The chlorophyll a content of C. vulgaris decreased with the increasing concentrations of metribuzin, puma and alachlor.

Acetamides↗

PubMed2006

T-lymphocyte profiles in FIV-infected wild lions and pumas reveal CD4 depletion.

Feline immunodeficiency virus (FIV) is a lentivirus related to human immunodeficiency virus (HIV) that causes feline AIDS in the domestic cat (Felis catus). Serological surveys indicate that at least 25 other species of cat possess antibodies that cross-react with domestic cat FIV. Most infected nondomestic cat species are without major symptoms of disease. Long-term studies of FIV genome variation and pathogenesis reveal patterns consistent with coadaptation of virus and host in free-ranging FIV-Ple-infected African lions (Panthera leo) and FIV-Pco-infected pumas (Puma concolor) populations. This report examined correlates of immunodeficiency in wild and captive lions and pumas by quantifying CD5(+), CD4(+), and CD8(+) T-cell subsets. Free-ranging FIV-Ple-infected lions had immunofluorescence flow cytometry (IFC) profiles marked by a dramatic decline in CD4(+) subsets, a reduction of the CD4(+)/CD8(+) ratio, reduction of CD8(+)beta(high) cells, and expansion of the CD8(+)beta(low) subset relative to uninfected lions. An overall significant depletion in CD5(+) T-cells in seropositive lions was linked with a compensatory increase in total CD5(-) lymphocytes. The IFC profiles were altered significantly in 50% of the seropositive individuals examined. The FIV-Pco-infected pumas had a more generalized response of lymphopenia expressed as a significant decline in total lymphocytes, CD5(+) T-cells, and CD5(-) lymphocytes as well as a significant reduction in CD4(+) T-cells. Like lions, seropositive pumas had a significant decline in CD8(+)beta(high) cells but differed by not having compensatory expansion of CD8(+)beta(low) cells relative to controls. Results from FIV-infected lions and pumas parallel human and Asian monkey CD4(+) diminution in HIV and SIV infection, respectively, and suggest there may be unrecognized immunological consequences of FIV infection in these two species of large cats.

Adaptation, Physiological↗

PubMed2003

Zebrafish puma mutant decouples pigment pattern and somatic metamorphosis.

The genetic and developmental bases for trait expression and variation in adults are largely unknown. One system in which genes and cell behaviors underlying adult traits can be elucidated is the larval-to-adult transformation of zebrafish, Danio rerio. Metamorphosis in this and many other teleost fishes resembles amphibian metamorphosis, as a variety of larval traits (e.g., fins, skin, digestive tract, sensory systems) are remodeled in a coordinated manner to generate the adult form. Among these traits is the pigment pattern, which comprises several neural crest-derived pigment cell classes, including black melanophores, yellow xanthophores, and iridescent iridophores. D. rerio embryos and early larvae exhibit a relatively simple pattern of melanophore stripes, but this pattern is transformed during metamorphosis into the more complex pattern of the adult, consisting of alternating dark (melanophore, iridophore) and light (xanthophore, iridophore) horizontal stripes. While it is clear that some pigment cells differentiate de novo during pigment pattern metamorphosis, the extent to which larval and adult pigment patterns are developmentally independent has not been known. In this study, we show that a subset of embryonic/early larval melanophores persists into adult stages in wild-type fish; thus, larval and adult pigment patterns are not completely independent in this species. We also analyze puma mutant zebrafish, derived from a forward genetic screen to isolate mutations affecting postembryonic development. In puma mutants, a wild-type embryonic/early larval pigment pattern forms, but supernumerary early larval melanophores persist in ectopic locations through juvenile and adult stages. We then show that, although puma mutants undergo a somatic metamorphosis at the same time as wild-type fish, metamorphic melanophores that normally appear during these stages are absent. The puma mutation thus decouples metamorphosis of the pigment pattern from the metamorphosis of many other traits. Nevertheless, puma mutants ultimately recover large numbers of melanophores and exhibit extensive pattern regulation during juvenile development, when the wild-type pigment pattern already would be completed. Finally, we demonstrate that the puma mutant is both temperature-sensitive and growth-sensitive: extremely severe pigment pattern defects result at a high temperature, a high growth rate, or both; whereas a wild-type pigment pattern can be rescued at a low temperature and a low growth rate. Taken together, these results provide new insights into zebrafish pigment pattern metamorphosis and the capacity for pattern regulation when normal patterning mechanisms go awry.

Animals↗

PubMed2003

Essential role for puma in development of postembryonic neural crest-derived cell lineages in zebrafish.

Multipotent neural crest stem cells have been identified in late gestation amniote embryos. Yet, significant questions remain about the mechanisms by which these cells are generated, maintained, and recruited during postembryonic development. The zebrafish, Danio rerio, offers an opportunity to identify genes essential for these processes, by screening for mutants with defects in traits likely to depend on these cells during metamorphosis and adult life. One such trait is the pigment pattern formed by neural crest-derived pigment cells, or chromatophores, which include black melanophores, yellow xanthophores, and iridescent iridophores. Previous analyses have demonstrated that the adult zebrafish pigment pattern depends on the de novo differentiation of latent precursor cells during both early and late phases of pigment pattern metamorphosis. To better understand the development of these cells, in this study, we analyze the zebrafish puma mutant, which ablates most of the adult melanophores that differentiate during metamorphosis, but leaves intact early larval melanophores that differentiate during embryogenesis. We use epistasis analyses to show that puma promotes the development of both early-appearing metamorphic melanophores that depend on the kit receptor tyrosine kinase, as well as late-appearing metamorphic melanophores that depend on both the G-protein-coupled endothelin receptor b1 (ednrb1) and the kit-related fms receptor tyrosine kinase. We further demonstrate that, during pigment pattern metamorphosis, puma mutants have deficiencies in the numbers of cells expressing transcripts for kit, ednrb1, and fms, as well as the HMG domain transcription factor sox10. Because the puma mutant phenotype is temperature-sensitive, we use temperature-shift experiments to identify a critical period for puma activity during pigment pattern metamorphosis. Finally, we use cell transplantations to show that puma acts cell-autonomously to promote the expansion of pigment cell lineages during metamorphosis. These results suggest a model for the lineage diversification of neural crest stem cells during zebrafish postembryonic development.

Animals↗

PubMed2003

PUMA in head and neck cancer.

Genetic alterations of p53, which monitors DNA damage and operates cellular checkpoints, is a major factor in the development of many types of cancer in human. PUMA, a direct mediator of p53-associated apoptosis, was recently identified. The PUMA gene was mapped to chromosomal arm 19q, a region frequently deleted in head/neck and lung cancers. We analyzed 30 primary tumors (15 head/neck and 15 lung) for loss of heterozygosity (LOH) at 19q using seven widely spaced microsatellite markers. LOH in at least one marker was present in 8 (56%) of the head/neck and 4 (26.6%) of the lung cancer samples. Overall, D19S408 and D19S412, showed the highest rates of allelic loss (23.3 and 16.6%, respectively). We then sequenced the entire coding region of the PUMA gene in all the 30 primary tumors and in 10 head/neck cancer cell lines. No mutations of PUMA were detected in any samples examined, regardless of the mutational status of the p53 gene. Forced expression of wild-type PUMA in JHU-012 and JHU-013 head/neck cancer cell lines significantly inhibited colony formation. Although PUMA suppresses tumor cell growth in head/neck cancer, it does not appear to be a direct target of inactivation in head and neck tumorigenesis.

Apoptosis Regulatory Proteins↗

PubMed2003

Puma is an essential mediator of p53-dependent and -independent apoptotic pathways.

Puma encodes a BH3-only protein that is induced by the p53 tumor suppressor and other apoptotic stimuli. To assess its physiological role in apoptosis, we generated Puma knockout mice by gene targeting. Here we report that Puma is essential for hematopoietic cell death triggered by ionizing radiation (IR), deregulated c-Myc expression, and cytokine withdrawal. Puma is also required for IR-induced death throughout the developing nervous system and accounts for nearly all of the apoptotic activity attributed to p53 under these conditions. These findings establish Puma as a principal mediator of cell death in response to diverse apoptotic signals, implicating Puma as a likely tumor suppressor.

Animals↗

PubMed2004

Suppression of tumorigenesis by the p53 target PUMA.

The p53 tumor suppressor regulates diverse antiproliferative processes such that cells acquiring p53 mutations have impaired cell-cycle checkpoints, senescence, apoptosis, and genomic stability. Here, we use stable RNA interference to examine the role of PUMA, a p53 target gene and proapoptotic member of the Bcl2 family, in p53-mediated tumor suppression. PUMA short hairpin RNAs (shRNAs) efficiently suppressed PUMA expression and p53-dependent apoptosis but did not impair nonapoptotic functions of p53. Like p53 shRNAs, PUMA shRNAs promoted oncogenic transformation of primary murine fibroblasts by the E1A/ras oncogene combination and dramatically accelerated myc-induced lymphomagenesis without disrupting p53-dependent cell-cycle arrest. However, the ability of PUMA to execute p53 tumor suppressor functions was variable because, in contrast to p53 shRNAs, PUMA shRNAs were unable to cooperate with oncogenic ras in transformation. These results demonstrate that the p53 effector functions involved in tumor suppression are context dependent and, in some settings, depend heavily on the expression of a single proapoptotic effector. Additionally, they demonstrate the utility of RNA interference for evaluating putative tumor suppressor genes in vivo.

Animals↗

PubMed2006

FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal.

Puma is an essential mediator of p53-dependent and -independent apoptosis in vivo. In response to genotoxic stress, Puma is induced in a p53-dependent manner. However, the transcription factor driving Puma up-regulation in response to p53-independent apoptotic stimuli has yet to be identified. Here, we show that FOXO3a up-regulates Puma expression in response to cytokine or growth factor deprivation. Importantly, dysregulated Akt signaling in lymphoid cells attenuated Puma induction upon cytokine withdrawal. Our results suggest that Puma, together with another BH3 only member, Bim, function as FOXO3a downstream targets to mediate a stress response when PI3K/Akt signaling is down-regulated.

Animals↗