CDK6—a review of the past and a glimpse into the future: from cell-cycle control to transcriptional regulation

Tigan, A-S; Bellutti, Florian; Kollmann, Karoline; Tebb, Graham; Sexl, Veronika

doi:10.1038/onc.2015.407

Cited by 148 publications

(141 citation statements)

References 166 publications

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“…CDK6 expression was downregulated in MAFB knockdown SW1116 cells, while CDKN3, CUL1 and CUL3 were upregulated (Figure 3A). This was consistent with the findings of other G1 phase arrest studies [21–24]. We also found that CCNB1 and CCND1 were downregulated (Supplementary Figure S3), which was in agreement with previous work [15].…”

Section: Resultssupporting

confidence: 94%

SUMOylated MAFB promotes colorectal cancer tumorigenesis

et al. 2016

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The transcription factor, v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB), promotes tumorigenesis in some cancers. In this study, we found that MAFB levels were increased in clinical colorectal cancer (CRC) samples, and higher expression correlated with more advanced TNM stage. We identified MAFB amplifications in a majority of tumor types in an assessment of The Cancer Genome Atlas database. Altered MAFB levels due to gene amplification, deletion, mutation, or transcription upregulation occurred in 9% of CRC cases within the database. shRNA knockdown experiments demonstrated that MAFB deficiency blocked CRC cell proliferation by arresting the cell cycle at G0/G1 phase in vitro. We found that MAFB could be SUMOylated by SUMO1 at lysine 32, and this modification was critical for cell cycle regulation by MAFB in CRC cells. SUMOylated MAFB directly regulated cyclin-dependent kinase 6 transcription by binding to its promoter. MAFB knockdown CRC cell xenograft tumors in mice grew more slowly than controls, and wild-type MAFB-overexpressing tumors grew more quickly than tumors overexpressing MAFB mutated at lysine 32. These data suggest that SUMOylated MAFB promotes CRC tumorigenesis through cell cycle regulation. MAFB and its SUMOylation process may serve as novel therapeutic targets for CRC treatment.

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Section: Resultssupporting

confidence: 94%

SUMOylated MAFB promotes colorectal cancer tumorigenesis

et al. 2016

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“…In addition, CDK6 can bind to chromatin and recruit binding motifs of transcription factors such as c-Jun, AP-1, P65 to induce the expression of the genes VEGF-A, EGR1, IL. However, cell cycle-independent functions for CDK6 are not shared with CDK4 [21]. In our study, we found CDK6 regulates the expression of p21 by promoting its promoter activity when CBX3 is deleted and its expression is not affected by CDK6 kinase activity.…”

Section: Discussionmentioning

confidence: 58%

“…The G1 kinases CDK4 and CDK6 are true cell-cycle kinases that regulate exit from the G1 phase of the cell cycle. They have received considerable attention as major drivers of cancer [21]. The study conducted by Kollmann et al reveals several novel roles for CDK6 acting as the kinase-independent in transcription.…”

Section: Discussionmentioning

confidence: 99%

“…Partial experiments demonstrate D-cyclins enhancing interaction with CDK2 or cyclinD-CDK4/CDK6-independent mechanism. However, several are also involved in transcriptional regulation, DNA damage repair, stem-cell self-renewal, metabolism, spermatogenesis and neuronal function [21]. Recent researches focus on the role of CDK6 in transcriptional regulation.…”

Section: Introductionmentioning

confidence: 99%

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CBX3 promotes colon cancer cell proliferation by CDK6 kinase-independent function during cell cycle

Fan

Liang

et al. 2017

Oncotarget

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Heterochromatin protein 1γ (CBX3) links histone methylation marks to transcriptional silence, DNA repair and RNA splicing, but a role for CBX3 in cancer remains largely unknown. In this study, we show that CBX3 in colon cancer cells promotes the progression of the cell cycle and proliferation in vitro and in vivo. Cell cycle (G1 phase to S phase) related gene CDK6 and p21 were further identified as targets of CBX3. In addition, we found that enhancing CDK6 suppresses cell proliferation by upregulating inhibitor p21 in the absence of CBX3, and this function is independent of the kinase activity of CDK6. Our results demonstrate a key role of CBX3 in colon carcinogenesis via suppressing the expression of CDK6/p21, which may disrupt the role of CDK6 in transcriptionally regulating p21, as part of a negative feedback loop to limit CDK6 excessive activation.

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“…CDK6 is known to have kinase independent functions 28, 29 ; however the close correlation between the dose of kinase inhibitor causing loss of pRb and the dose blocking cell proliferation supports the premise that the kinase function of CDK6 is essential for resistance. Interestingly, overexpression of CDK4 was never observed in the models and enforced overexpression of CDK4 did not promote inhibitor resistance.…”

Section: Discussionmentioning

confidence: 99%

Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence

et al. 2016

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Dysregulated activation of the CDK4/6 kinases is a hallmark of most mammary-derived carcinomas. ATP competitive inhibitors against this complex have been recently advanced in the clinic and shown significant activity, particularly against tumors driven by the estrogen receptor (ER). However, resistance to these compounds has begun to emerge often months to years after their initiation. We investigated potential mechanisms of resistance utilizing cell line models which are highly sensitive to this class of drugs. After prolonged exposure to the selective and potent CDK4/6 inhibitor LY2835219, clones emerged and several were found to harbor amplification of the CDK6 kinase. Amplification of CDK6 resulted in a marked increase in CDK6 expression and reduced response of the CDK4/6 target, pRb, to CDK4/6 inhibitors. Knockdown of CDK6 restored drug sensitivity while enforced overexpression of CDK6 was sufficient to mediate drug resistance. Not only did CDK6 overexpression mediate resistance to CDK4/6 inhibitors, it also led to reduced expression of the ER and progesterone receptor (PR), and diminished responsiveness to ER antagonism. The reduced ER/PR expression after CDK4/6 inhibitor resistance was additionally observed in tumor biopsy specimens from patients treated with these drugs. Alternative mechanisms of resistance to CDK4/6 inhibitors such as loss of pRb and Cyclin E1 overexpression also exhibited decreased hormone responsiveness suggesting that the clinical paradigm of sequential endocrine-based therapy may be ineffective in some settings of acquired CDK4/6 resistance.

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CDK6—a review of the past and a glimpse into the future: from cell-cycle control to transcriptional regulation

Cited by 148 publications

References 166 publications

SUMOylated MAFB promotes colorectal cancer tumorigenesis

SUMOylated MAFB promotes colorectal cancer tumorigenesis

CBX3 promotes colon cancer cell proliferation by CDK6 kinase-independent function during cell cycle

Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence

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