Limited overlapping roles of P15INK4b and P18INK4c cell cycle inhibitors in proliferation and tumorigenesis

Abstract

Entry of quiescent cells into the cell cycle is driven by the cyclin D-dependent kinases Cdk4 and Cdk6. These kinases are negatively regulated by the INK4 cell cycle inhibitors. We report the generation of mice defective in P15 INK4b and P18 INK4c . Ablation of these genes, either alone or in combination, does not abrogate cell contact inhibition or senescence of mouse embryo ®broblasts in culture. However, loss of P15 INK4b , but not of P18 INK4c , confers proliferative advantage to these cells and makes them more sensitive to transformation by H-ras oncogenes. In vivo, ablation of P15 INK4b and P18 INK4c genes results in lymphoproliferative disorders and tumor formation. Mice lacking P18 INK4c have deregulated epithelial cell growth leading to the formation of cysts, mostly in the cortical region of the kidneys and the mammary epithelium. Loss of both P15 INK4b and P18 INK4c does not result in signi®cantly distinct phenotypic manifestations except for the appearance of cysts in additional tissues. These results indicate that P15 INK4b and P18 IKN4c are tumor suppressor proteins that act in different cellular lineages and/or pathways with limited compensatory roles.

The logic of TGFβ signaling

“…Loss of the ultimate effector of TGFb cyto-static inputs, the tumor suppressor RB, confers resistance to TGFb only in some cases [6,98], while the loss of other interconnected tumor suppressors including p53, p16Ink4a, ARF or p27Kip1 has little effect. Due to functional redundancies, TGFb remains a potent growth inhibitor in cells that lack p15Ink4b [99] or the c-Myc response [43]. Interestingly, however, the combined loss of these two gene responses correlates with evasion of cytostasis in breast cancer cell lines [46].…”

Ink4c is dispensable for tumor suppression in Myc-induced B-cell lymphomagenesis

“…Here, we interrogated the role of the Ink4 family member p18 Ink4c in Em-Myc-induced B-cell lymphomas, especially given that loss or haploinsufficiency of Ink4c supports its role as a tumor suppressor, and because Ink4c-deficient mice resemble, in many respects, Kip1-deficient animals (Fero et al, 1996;Kiyokawa et al, 1996;Franklin et al, 1998;Latres et al, 2000). Several pieces of evidence implicate p18 Ink4c as a tumor suppressor in B cells.…”

“…By preventing the phosphorylation of the retinoblastoma family proteins (Rb, p107 and p130) by cyclin-D-cdk4/6 or cyclin-E/cdk2 complexes, these CKIs enforce transcriptional repression by E2F complexes, thereby preventing entry into the S-phase. Of the four Ink4 family members (p16 Ink4a , p15 Ink4b , p18 Ink4c and p19 Ink4d ), the first three possess tumor suppressor activities in humans and mice (Franklin et al, 1998;Ruas and Peters, 1998;Latres et al, 2000;Krimpenfort et al, 2001;Sharpless et al, 2001). Interestingly, the Ink4a locus encodes another tumor suppressor, p19 Arf (p14 ARF in humans), which shares exons 2 and 3 with p16 Ink4a but which is initiated from an alternative upstream exon (1b) and is translated in an alternative reading frame (Quelle et al, 1995).…”

“…For example, Ink4c-knockout mice develop pituitary adenomas with 100% penetrance and, with a lesser incidence, develop testicular tumors and B-cell lymphoma (Franklin et al, 1998;Latres et al, 2000). Loss of Ink4c collaborates with the loss of p53 or Patched-1 in the induction of medulloblastoma (Uziel et al, 2005) and with p53 loss in hemangiosarcoma (Zindy et al, 2003;Damo et al, 2005).…”

INK4 Family —A promising target for ‘gene-regulating chemoprevention’ and ‘molecular-targeting prevention’ of cancer

“…From these findings, it was suggested that p16 INK4a , and not p18 INK4c , plays a role in tumor suppression in humans. However, p18 INK4c -deficient mice exhibit frequent development of a wide spectrum of tumors, establishing p18 INK4c as a tumor-suppressor gene at least in mice (33,34). Furthermore, it was recently reported that treatment of p18 INK4c null and heterozygous mice with a chemical carcinogen causes tumorigenesis at an accelerated rate (35).…”