Genetic ablation of Cyclin D1 abrogates genesis of rhabdoid tumors resulting from Ini1 loss

Mary Tsikitis, Zhikai Zhang, Winfried Edelman, David Zagzag, Ganjam V. Kalpana

Research output: Contribution to journalArticlepeer-review

95 Scopus citations


Rhabdoid tumors are aggressive pediatric malignancies for which, currently, there are no effective or standard treatment strategies. Rhabdoid tumors arise because of the loss of the tumor suppressor gene INI1. We have previously demonstrated that INI1 represses Cyclin D1 transcription in rhabdoid cells by directly recruiting histone deacetylase 1 complex to its promoter, leading to G0-G1 arrest. Expression of Cyclin D1 overcomes cell cycle arrest mediated by INI1 and Cyclin D1 overexpression in human rhabdoid tumors is a common phenomenon. However, it is not clear whether Cyclin D1 is a critical downstream target of INI1 in vivo and whether the derepression of this gene is essential for rhabdoid tumorigenesis. To determine the requirement of Cyclin D1 for genesis of rhabdoid tumors in vivo, we developed Ini1 heterozygous mice by targeted disruption. We found that the tumors developed in these Ini1+/-mice are rhabdoid, defective for Ini1 protein, and like the human tumors, express Cyclin D1. We crossed Ini1+/- mice to Cyclin D1-/- mice and found that Ini1+/- mice with Cyclin D1 deficiency did not develop any spontaneous tumors, in contrast to the parental Ini1+/- mice. These results strongly support the hypothesis that Cyclin D1 is a key mediator in the genesis of rhabdoid tumors. Our results provide an in vivo proof of concept that drugs that target Cyclin D1 expression or activity could be potentially effective as novel therapeutic agents for rhabdoid tumors.

Original languageEnglish (US)
Pages (from-to)12129-12134
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number34
StatePublished - Aug 23 2005


  • Atypical teratoid
  • Cell cycle
  • Ini1/hSNF5
  • Tumorigenesis

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Genetic ablation of Cyclin D1 abrogates genesis of rhabdoid tumors resulting from Ini1 loss'. Together they form a unique fingerprint.

Cite this