Cancer-associated mis-sense and deletion mutations impair p16INK4 CDK inhibitory activity.


:The p16INK4 gene is a candidate tumour-suppressor gene which maps to the genomic locus 9p21, and mutations of this gene are associated with melanoma and other cancers. Biochemical studies suggest that p16INK4 mediates its effects by specifically inhibiting the G1 cyclin-dependent kinases CDK4 and CDK6, thereby regulating the progression through G1 into S phase of the cell cycle. To evaluate the functional effects of mutations in p16INK4 which have been observed in primary cancers and cancer cell lines, we constructed a series of deletion mutants comprising amino acid regions 9-72, 9-131, 73-131 and 73-156; a mis-sense mutation identified in melanoma (Arg87Pro); and the polymorphism Ala48Thr and investigated their ability to inhibit cyclin D1/CDK4 kinase activity in vitro. Removal of 25 amino acids from the carboxy terminus of p16INIK4 (9-131) had little impact on its inhibitory activity. In contrast, deletion of the 65 N-terminal amino acids comprising the first and second ankyrin repeats of p16INK4 (73-131) abolished its inhibitory activity. The carboxy (73-156) and amino termial (9-72) fragments of p16INK4 also failed to inhibit cyclin D1/CDK4 activity. These results indicate that the core region (73-131) as well as amino acids N-terminal of this sequence are important, whereas sequences C-terminal of amino acid 131 are less important for the inhibitory activity of this molecule. The melanoma-associated Arg87Pro mutation resulted in loss of inhibitory activity, whereas the Ala148Thr polymorphic variant was as effective as the alanine variant of p16INK4 in inhibiting D1/CDK4 kinase activity. Binding assays revealed that inhibition was invariably associated with p16INK4 binding to CDK4. Hence, our studies indicate that minor perturbations in p16INK4 primary structure can lead to loss of its inhibitory activity, possibly contributing to oncogenesis in numerous cell types.


Int J Cancer


Lilischkis R,Sarcevic B,Kennedy C,Warlters A,Sutherland RL




Has Abstract


1996-04-10 00:00:00














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    abstract::Evidence from randomized controlled trials suggests that calcium may protect against recurrence of colorectal adenomas, which could lead to the subsequent prevention of cancer. Yet the trials used only a large single dose and were of small sizes, and thus, knowledge of the dose-response relationship and influence on h...

    journal_title:International journal of cancer

    pub_type: 杂志文章,meta分析


    authors: Keum N,Lee DH,Greenwood DC,Zhang X,Giovannucci EL

    更新日期:2015-04-01 00:00:00

  • Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients.

    abstract::We previously reported that some single nucleotide polymorphisms (SNPs) of candidate genes involved in the MTOR complex1 (MTORC1) were associated with risk of gastric cancer (GCa). In the present study, we further evaluated associations of eight potentially functional SNPs of MTOR, MLST8 and RPTOR with survival of 100...

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    authors: Cheng L,Qiu L,Zhang R,Qian D,Wang M,Sun M,Zhu X,Wang Y,Guo W,Wei Q

    更新日期:2019-01-15 00:00:00

  • Bladder Cancer Risk Associated with Family History of Cancer.

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    journal_title:International journal of cancer

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    authors: Koutros S,Decker KL,Baris D,Pardo LA,Johnson A,Hosain GMM,Rothman N,Karagas MR,Schwenn MR,Silverman DT

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    journal_title:International journal of cancer

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    authors: Roswall N,Freisling H,Bueno-de-Mesquita HB,Ros M,Christensen J,Overvad K,Boutron-Ruault MC,Severi G,Fagherazzi G,Chang-Claude J,Kaaks R,Steffen A,Boeing H,Argüelles M,Agudo A,Sánchez MJ,Chirlaque MD,Barricarte Gurrea A

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  • Lysine-specific demethylase-1 contributes to malignant behavior by regulation of invasive activity and metabolic shift in esophageal cancer.

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    authors: Kosumi K,Baba Y,Sakamoto A,Ishimoto T,Harada K,Nakamura K,Kurashige J,Hiyoshi Y,Iwatsuki M,Iwagami S,Sakamoto Y,Miyamoto Y,Yoshida N,Oki E,Watanabe M,Hino S,Nakao M,Baba H

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    authors: Moerman CJ,Berns MP,Bueno de Mesquita HB,Runia S

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  • Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer.

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    journal_title:International journal of cancer

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    pub_type: 杂志文章


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    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Hu Y,Correa AM,Hoque A,Guan B,Ye F,Huang J,Swisher SG,Wu TT,Ajani JA,Xu XC

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    journal_title:International journal of cancer

    pub_type: 杂志文章,评审


    authors: Ruan Q,Wang H,Burke LJ,Bridle KR,Li X,Zhao CX,Crawford DHG,Roberts MS,Liang X

    更新日期:2020-09-15 00:00:00

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    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Desgranges C,Pi GH,Bornkamm GW,Legrand C,Zeng Y,de-Thé G

    更新日期:1983-11-15 00:00:00