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- W4361247444 abstract "<div>Abstract<p>The INK4 and CIP cyclin-dependent kinase (Cdk) inhibitors (CKI) activate pocket protein function by suppressing Cdk4 and Cdk2, respectively. Although these inhibitors are lost in tumors, deletion of individual CKIs results in modest proliferation defects in murine models. We have evaluated cooperativity between loss of all INK4 family members (using <i>cdk4r24c</i> mutant alleles that confer resistant to INK4 inhibitors) and p21<sup>Waf1/Cip1</sup> in senescence and transformation of mouse embryo fibroblasts (MEF). We show that mutant cdk4r24c and p21 loss cooperate in pRb inactivation and MEF immortalization. Our studies suggest that <i>cdk4r24c</i> mediates resistance to p15<sup>INK4B</sup>/p16<sup>INK4A</sup> that accumulates over passage, whereas loss of p21 suppresses hyperoxia-induced Cdk2 inhibition and pRb dephosphorylation on MEF explantation in culture. Although <i>cdk4r24c</i> and <i>p21</i> loss cooperate in <i>H-ras<sup>V12</sup>/c-myc</i>–induced foci formation, they are insufficient for oncogene-induced anchorage-independent growth. Interestingly, <i>p21<sup>−/−</sup>; cdk4r24c</i> MEFs expressing <i>H-ras<sup>V12</sup></i> and <i>c-myc</i> display detachment-induced apoptosis and are transformed by <i>c-myc, H-ras<sup>V12</sup></i>, and <i>Bcl-2</i>. We conclude that the INK4 family and <i>p21</i> loss cooperate in promoting pRb inactivation, cell immortalization, and <i>H-ras<sup>V12</sup>/c-myc</i>–induced loss of contact inhibition. In addition, absence of pRb function renders <i>H-ras<sup>V12</sup></i> + <i>c-myc</i>–transduced fibroblasts prone to apoptosis when deprived of the extracellular matrix, and oncogene-induced anchorage-independent growth of pocket protein–deficient cells requires apoptotic suppression. [Cancer Res 2007;67(9):4130–7]</p></div>" @default.
- W4361247444 created "2023-03-31" @default.
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- W4361247444 date "2023-03-30" @default.
- W4361247444 modified "2023-09-25" @default.
- W4361247444 title "Data from <i>p21</i> Loss Cooperates with INK4 Inactivation Facilitating Immortalization and <i>Bcl-2</i>–Mediated Anchorage-Independent Growth of Oncogene-Transduced Primary Mouse Fibroblasts" @default.
- W4361247444 doi "https://doi.org/10.1158/0008-5472.c.6496293" @default.
- W4361247444 hasPublicationYear "2023" @default.
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