INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions

Abstract

SummaryThe cyclin D-Cdk4-6/INK4/Rb/E2F pathway plays a key role in controlling cell growth by integrating multiple mitogenic and antimitogenic stimuli . The members of INK4 family, comprising p16 INK4a , p15 INK4b , p18 INK4c , and p19 INK4d , block the progression of the cell cycle by binding to either Cdk4 or Cdk6 and inhibiting the action of cyclin D. These INK4 proteins share a similar structure dominated by several ankyrin repeats. Although they appear to be structurally redundant and equally potent as inhibitors, the INK4 family members are differentially expressed during mouse development. The striking diversity in the pattern of expression of INK4 genes suggested that this family of cell cycle inhibitors might have cell lineage-specific or tissue-specific functions. The INK4 proteins are commonly lost or inactivated by mutations in diverse types of cancer, and they represent established or candidate tumor suppressors. Apart from their capacity to arrest cells in the G1-phase of the cell cycle they have been shown to participate in an increasing number of cellular processes. Given their emerging roles in fundamental physiological as well as pathological processes, it is interesting to explore the diverse roles for the individual INK4 family members in different functions other than cell cycle regulation. Extensive studies, over the past few years, uncover the involvement of INK4 proteins in senescence, apoptosis, DNA repair, and multistep oncogenesis. We will focus the discussion here on these unexpected issues.IUBMB Life, 59: 419-426, 2007

P16INK4A immunostaining is a strong indicator for high‐risk‐HPV‐associated oropharyngeal carcinomas and dysplasias, but is unreliable to predict low‐risk‐HPV‐infection in head and neck papillomas and laryngeal dysplasias

“…These include infection with other viruses (i.e., cytomegalovirus and adenovirus), which functionally inactivate pRb in a similar fashion as the HPV-oncogene E7, 49,50 physiological stress, oncogene-driven senescence by functional overactivation of (proto)oncogenes including Ras, Raf, MEK and E2F or replicative senescence due to DNA-damage or oxidative stress. [51][52][53][54] In summary, our results indicate that a strong nuclear and cytoplasmic p16 INK4A immunostaining pattern can accurately predict the presence of HR-HPV16 in OPSCC and tonsillar dysplasias. Our data underscore the proposed cut-off level of 70% p16 INK4A positive cells, corresponding to block positive p16 INK4A immunopositivity, in these lesions as indicator for HR-HPV16-presence.…”

Structural model of the dimeric Parkinson’s protein LRRK2 reveals a compact architecture involving distant interdomain contacts

“…Furthermore, the top-scoring docking solutions for the ankyrin domain to the kinase domain resemble the structure determined for a complex from the ankyrin-repeat protein INK4 and the kinase domain of CDK6 (41). INK4 proteins are well-characterized tumor suppressors that inhibit cyclin kinases (44). In addition, based on the LRRK2 primary protein sequence, the LRR domain is directly coupled to both the C terminus of the ankyrin domain and the N terminus of the Roc G-domain.…”

p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors

“…In addition, p16 Ink4a overexpression has been reported in senescent fibroblasts , in response to oxidative stress (Ksiazek et al, 2006;Quereda et al, 2007), DNA damage and changes in chromatin structure (Canepa et al, 2007;Fordyce et al, 2010). Nonetheless, a complete understanding of the signals that trigger senescence is currently lacking, and although p16 Ink4a appears to be one of the principal factors in senescence, more information is needed to ascertain the exact role of each factor in this process.…”