Reviewing the current classification of inhibitor of growth family proteins

Abstract

Inhibitor of growth (ING) family proteins have been defined as candidate tumor suppressors for more than a decade. Recent emerging results using siRNA and knockout mice are expanding the previous understanding of this protein family. The results of ING1 knockout mouse experiments revealed that ING1 has a protective effect on apoptosis. Our recent results showed that ING2 is overexpressed in colorectal cancer, and induces colon cancer cell invasion through an MMP13-dependent pathway. Knockdown of ING2 by siRNA induces premature senescence in normal human fibroblast cells, and apoptosis or cell cycle arrest in various adherent cancer cells. Taken together, these results suggest that ING2 may also have roles in cancer progression and/or malignant transformation under some conditions. Additionally, knockdown of ING4 and ING5 by siRNA shows an inhibitory effect on the transition from G(2)/M to G(1) phase and DNA replication, respectively, suggesting that these proteins may play roles during cell proliferation in some context. ING family proteins may play dual roles, similar to transforming growth factor-beta, which has tumor suppressor-like functions in normal epithelium and also oncogenic functions in invasive metastatic cancers. In the present article, we briefly review ING history and propose a possible interpretation of discrepancies between past and recent data.

Figure 1

Structure of inhibitor of growth (ING) family genes. (a) Structure of the ING1 gene and four splice variants of ING1 from the gene. (b) Structure of the ING2 gene and two splice variants of ING2 from the gene. (c) Structure of the ING4 gene and eight splice variants of ING1 from the gene.

Figure 2

A model of signaling pathways mediated by inhibitor of growth (ING) family proteins. ING family proteins can associate with histone deacetylase (HDAC), histone acetyltransferase (HAT), and histone methyltransferase (HMT). This family of proteins is also associated with DNA methylation status, transcription factors, and chromatin structure affected by histone modification status. Through these complicated associations, ING family proteins generate a ‘histone code’ depending on the local situation, leading to transcriptional activation or suppression. Regardless of the effect on transcription, ING family proteins play very important roles in maintaining cellular homeostasis and survival.

Figure 3

A model of the inhibitor of growth (ING) 2 signaling pathway. (a) In normal cells, retinol binding protein (RBP) 1 may allow recruitment of the mSin3–histone deacetylase (HDAC) complex by retinoblastoma (Rb) tumor suppressor proteins to induce cell cycle arrest by repressing E2F‐dependent transcription and DNA replication origins. The tumor suppressor p53 also monitors abnormal cell proliferation through suppression of genes associates with cell proliferation, including ING2 (ING2a). (b) In cancer cells, upregulated ING2 may recruit sirtuin (SIRT) 1 to the RBP1–mSin3–HDAC complex. The recruited SIRT1 may inhibit RBP1‐associated mSin3A–HDAC1 activity, leading to activation of E2F. The activated E2F may promote cell proliferation. Upregulated ING2 (ING2a) may suppress p53 functions to facilitate exacerbation of cancers.