human
The task is to decide the Hallmarks of Cancer (HOC) taxonomy of the article based on its abstract. The input is an abstract text. There are 10 topics you will need to decide whether the article is related to. Topics: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genomic instability and mutation, tumor promoting inflammation, cellular energetics, avoiding immune destruction. The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics.
    ###
    INPUT: Although the p16(INK4a) and p21Waf1/Cip1 cyclin-dependent kinase ( CDK ) inhibitors are known to play key roles in cellular senescence in vitro , their roles in senescence remain rather poorly understood in vivo . This situation is partly due to the possibility of compensatory effect(s) between p16INK4a and p21Waf1/Cip1 or to the upregulation of functionally related CDK inhibitors . To directly address the cooperative roles of p16INK4a and p21Waf1/Cip1 in senescence in vivo , we generated a mouse line simply lacking both p16INK4a and p21Waf1/Cip1 genes [ double-knockout ( DKO) ] . Mouse embryonic fibroblasts ( MEF ) derived from DKO mice displayed no evidence of cellular senescence when cultured serially in vitro . Moreover , DKO MEFs readily escaped Ras-induced senescence and overrode contact inhibition in culture . This was not the case in MEFs lacking either p16INK4a or p21Waf1/Cip1 , indicating that p16(INK4a) and p21Waf1/Cip1 play cooperative roles in cellular senescence and contact inhibition in vitro . Notably , we found the DKO mice to be extremely susceptible to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin carcinogenesis that involves oncogenic mutation of the H-ras gene . Mechanistic investigations suggested that the high incidence of cancer in DKO mice likely reflected a cooperative effect of increased benign skin tumor formation caused by p21Waf1/Cip1 loss , with increased malignant conversion of benign skin tumors caused by p16(INK4a) loss . Our findings establish an intrinsic cooperation between p16INK4a and p21Waf1/Cip1 in the onset of cellular senescence and tumor suppression in vivo .
    OUTPUT:

agent
enabling replicative immortality;evading growth suppressors;genomic instability and mutation
The task is to decide the Hallmarks of Cancer (HOC) taxonomy of the article based on its abstract. The input is an abstract text. There are 10 topics you will need to decide whether the article is related to. Topics: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genomic instability and mutation, tumor promoting inflammation, cellular energetics, avoiding immune destruction. The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics.
    ###
    INPUT: Although the p16(INK4a) and p21Waf1/Cip1 cyclin-dependent kinase ( CDK ) inhibitors are known to play key roles in cellular senescence in vitro , their roles in senescence remain rather poorly understood in vivo . This situation is partly due to the possibility of compensatory effect(s) between p16INK4a and p21Waf1/Cip1 or to the upregulation of functionally related CDK inhibitors . To directly address the cooperative roles of p16INK4a and p21Waf1/Cip1 in senescence in vivo , we generated a mouse line simply lacking both p16INK4a and p21Waf1/Cip1 genes [ double-knockout ( DKO) ] . Mouse embryonic fibroblasts ( MEF ) derived from DKO mice displayed no evidence of cellular senescence when cultured serially in vitro . Moreover , DKO MEFs readily escaped Ras-induced senescence and overrode contact inhibition in culture . This was not the case in MEFs lacking either p16INK4a or p21Waf1/Cip1 , indicating that p16(INK4a) and p21Waf1/Cip1 play cooperative roles in cellular senescence and contact inhibition in vitro . Notably , we found the DKO mice to be extremely susceptible to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin carcinogenesis that involves oncogenic mutation of the H-ras gene . Mechanistic investigations suggested that the high incidence of cancer in DKO mice likely reflected a cooperative effect of increased benign skin tumor formation caused by p21Waf1/Cip1 loss , with increased malignant conversion of benign skin tumors caused by p16(INK4a) loss . Our findings establish an intrinsic cooperation between p16INK4a and p21Waf1/Cip1 in the onset of cellular senescence and tumor suppression in vivo .
    OUTPUT:
